Cardiac sarcomere inhibitor oral formulations

ABSTRACT

Provided herein are formulations comprising cardiac sarcomere inhibitor (R)-N-(5-(5-ethyl-1,2,4-oxadia-zol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, processes for making such formulations, and methods of treating various cardiac diseases and conditions with such formulations.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional PatentApplication No. 62/875,358, filed Jul. 17, 2019, the disclosure of whichis hereby incorporated herein by reference in its entirety.

FIELD

Provided herein are formulations comprising cardiac sarcomere inhibitor(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,processes for making such formulations, and methods of treating variouscardiac diseases and conditions with such formulations.

BACKGROUND

The cardiac sarcomere is the basic unit of muscle contraction in theheart. The cardiac sarcomere is a highly ordered cytoskeletal structurecomposed of cardiac muscle myosin, actin and a set of regulatoryproteins. Cardiac muscle myosin is the cytoskeletal motor protein in thecardiac muscle cell. It is directly responsible for converting chemicalenergy into the mechanical force, resulting in cardiac musclecontraction. The cardiac sarcomere is composed of a network ofcontractile and structural proteins that regulate cardiac musclefunction. The components of the cardiac sarcomere present targets forthe treatment of various cardiac diseases and conditions, for example byincreasing contractility or facilitating complete relaxation to modulatesystolic and diastolic function, respectively. The force and speed ofcardiac muscle contraction is a major determinant of organ function andis modulated by the cyclical interactions of actin and myosin.Regulation of actin and myosin binding is determined by a network ofmyofilament regulatory proteins and the level of intracellular Ca²⁺. Thetroponin complex and tropomyosin are thin filament proteins which governthe availability of actin binding sites, and the essential andregulatory light chains, and myosin binding protein C modulate theposition and mechanical properties of myosin.

Abnormalities in the cardiac sarcomere have been identified as thedriving cause for a variety of cardiac diseases and conditions, such ashypertrophic cardiomyopathy (HCM) and heart failure with preservedejection fraction (HFpEF). Mutations in the proteins of the sarcomerecause disease by rendering the cardiac muscle either ‘hyper’ or ‘hypo’contractile. Modulators of the cardiac sarcomere can be used torebalance contractility and stop or reverse the course of disease.

Current agents that target the cardiac sarcomere, such as inotropes(drugs that increase the contractile ability of the heart) are poorlyselective for cardiac tissue, which leads to recognized adverse effectsthat limit their use. These adverse effects include cell damage causedby an increased rate of energy expenditure, exacerbation of relaxationabnormalities, and potential arrhythmogenic side effects that may resultfrom increased cytosolic Ca++ and cyclic AMP concentrations in theinotropically stimulated myocardium. Given the limitations of currentagents, new approaches are needed to improve cardiac function in HCM andHFpEF.

There remains a great need for agents that exploit new mechanisms ofaction and may have better outcomes in terms of relief of symptoms,safety, and subject mortality, both short-term and long-term. New agentswith an improved therapeutic index over current agents will provide ameans to achieve these clinical outcomes. The selectivity of agentsdirected at the cardiac sarcomere (for example, by targeting cardiacmyosin) has been identified as an important means to achieve thisimproved therapeutic index.

Newly developed cardiac sarcomere inhibitors are described inInternational Application No. PCT/US2019/014344, published as WO2019/144041, which is incorporated herein by reference. Specifically,International Application No. PCT/US2019/014344 describes a genus ofcompounds, including the compound(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,having the structure:

The present disclosure provides formulations comprising the cardiacsarcomere inhibitor(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideis a selective allosteric inhibitor of cardiac myosin that has little tono effect on smooth muscle myosin. Benefits of this compound include awide therapeutic index, low impact on cardiac relaxation, andadvantageous pharmacokinetic and safety profiles. The present disclosurealso provides processes for making formulations comprising the compound(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideand methods of treating various cardiac diseases and conditions withsuch formulations, such as for example methods of treating heart failureincluding HCM and HFpEF.

SUMMARY

In one aspect, provided is a formulation comprising: (i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) a filler; (iii) a binder; (iv) a disintegrant; (v) asurfactant; and (vi) a lubricant.

In another aspect, provided is a formulation comprising: (i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) a filler; (iii) a binder; (iv) a disintegrant; (v) a surfactant;and (vi) a lubricant.

In another aspect, provided is a tablet comprising: (i) a core having atotal core weight comprising: (a) an intra-granular componentcomprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) an intra-granular filler; (a-iii) an intra-granularbinder; (a-iv) an intra-granular disintegrant; and (a-v) anintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) an extra-granular filler; (b-ii) an extra-granulardisintegrant; and (b-iii) an extra-granular lubricant; and optionally(ii) a coating layer comprising a coating agent.

In yet another aspect, provided is a tablet comprising: (i) a corehaving a total core weight comprising: (a) an intra-granular componentcomprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) an intra-granular filler; (a-iii) an intra-granular binder;(a-iv) an intra-granular disintegrant; and (a-v) an intra-granularsurfactant; and (b) an extra-granular component comprising: (b-i) anextra-granular filler; (b-ii) an extra-granular disintegrant; and(b-iii) an extra-granular lubricant; and optionally (ii) a coating layercomprising a coating agent.

In yet another aspect, provided is a process for making a tabletcomprising: (i) a core having a total core weight comprising: (a) anintra-granular component comprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) an intra-granular filler; (a-iii) an intra-granularbinder; (a-iv) an intra-granular disintegrant; and (a-v) anintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) an extra-granular filler; (b-ii) an extra-granulardisintegrant; and (b-iii) an extra-granular lubricant; and (ii) acoating layer comprising a coating agent, wherein the process comprises:(1) preparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant; (2)milling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant to formthe intra-granular component; (3) blending the intra-granular componentwith the extra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant to form a final blend mixture; (4) compressingthe final blend mixture to form the core; and (5) coating the core withthe coating layer.

In yet another aspect, provided is a process for making a tabletcomprising: (i) a core having a total core weight comprising: (a) anintra-granular component comprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) an intra-granular filler; (a-iii) an intra-granular binder;(a-iv) an intra-granular disintegrant; and (a-v) an intra-granularsurfactant; and (b) an extra-granular component comprising: (b-i) anextra-granular filler; (b-ii) an extra-granular disintegrant; and(b-iii) an extra-granular lubricant; and (ii) a coating layer comprisinga coating agent, wherein the process comprises: (1) preparing granulescomprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant; (2) milling thegranules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant to form theintra-granular component; (3) blending the intra-granular component withthe extra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant to form a final blend mixture; (4) compressingthe final blend mixture to form the core; and (5) coating the core withthe coating layer.

In yet other aspects, provided are methods of treating heart disease ina subject in need thereof, the method including administering to thesubject a formulation described herein or a tablet described herein. Insome embodiments, the heart disease is hypertrophic cardiomyopathy(HCM). In some embodiments, the HCM is obstructive or nonobstructive oris caused by sarcomeric and/or non-sarcomeric mutations. In someembodiments, the heart disease is heart failure with preserved ejectionfraction (HFpEF). In some embodiments, the heart disease is selectedfrom the group consisting of diastolic dysfunction, primary or secondaryrestrictive cardiomyopathy, myocardial infarction and angina pectoris,and left ventricular outflow tract obstruction. In some embodiments, theheart disease is hypertensive heart disease, congenital heart disease,cardiac ischemia, coronary heart disease, diabetic heart disease,congestive heart failure, right heart failure, cardiorenal syndrome, orinfiltrative cardiomyopathy. In some embodiments, the heart disease is acondition that is or is related to cardiac senescence and/or diastolicdysfunction due to aging. In some embodiments, the heart disease is acondition that is or is related to left ventricular hypertrophy and/orconcentric left ventricular remodeling.

Provided in other aspects are methods of treating a disease or conditionassociated with HCM in a subject in need thereof, wherein the methodinvolves administering to the subject a formulation described herein ora tablet described herein. In some embodiments, the disease or conditionis selected from the group consisting of Fabry's Disease, Danon Disease,mitochondrial cardiomyopathies, and Noonan Syndrome.

Provided in some aspects are methods of treating a disease or conditionthat is associated with secondary left ventricular wall thickening in asubject in need thereof, wherein the method involves administering tothe subject a formulation described herein or a tablet described herein.In some embodiments, the disease or condition is selected from the groupconsisting of hypertension, valvular heart diseases (aortic stenosis,Mitral valve regurgitation), metabolic syndromes (diabetes, obesity),end stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry'sdisease, Friedreich Ataxia, Danon disease, Noonan syndrome, and Pompedisease.

Provided in other aspects are methods of treating a disease or conditionthat is associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis, wherein the method involves administeringto the subject a formulation described herein or a tablet describedherein. Also provided are methods of treating muscular dystrophies(e.g., Duchenne muscular dystrophy) or glycogen storage diseases.

Also provided are methods of inhibiting the cardiac sarcomere in asubject in need thereof, wherein the method involves administering tothe subject a formulation described herein or a tablet described herein.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 presents a flow chart illustrating Unit Operations in thepreparation of a formulation described herein.

FIG. 2 presents a flow chart illustrating Unit Operations in thepreparation of a non-coated tablet described herein.

FIG. 3 presents a flow chart illustrating Unit Operations in thepreparation of a coated tablet described herein.

DETAILED DESCRIPTION Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

The term “pharmaceutically acceptable salt” refers to a salt of any ofthe compounds herein which are known to be non-toxic and are commonlyused in the pharmaceutical literature. In some embodiments, thepharmaceutically acceptable salt of a compound retains the biologicaleffectiveness of the compounds described herein and are not biologicallyor otherwise undesirable. Examples of pharmaceutically acceptable saltscan be found in Berge et al., Pharmaceutical Salts, J. PharmaceuticalSciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, andphosphoric acid. Organic acids from which salts can be derived include,for example, acetic acid, propionic acid, glycolic acid, pyruvic acid,lactic acid, oxalic acid, malic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid andsalicylic acid. Pharmaceutically acceptable base addition salts can beformed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines; substituted aminesincluding naturally occurring substituted amines; cyclic amines; andbasic ion exchange resins. Examples of organic bases includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is selected fromammonium, potassium, sodium, calcium, and magnesium salts.

If the compound described herein is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the compound is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds (see,e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences,January 1977, 66(1), 1-19). Those skilled in the art will recognizevarious synthetic methodologies that may be used to preparepharmaceutically acceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Suitable solvents include, for example, water and alcohols (e.g.,ethanol). Solvates include hydrates having any ratio of compound towater, such as monohydrates, dihydrates and hemi-hydrates.

The term “hydrate” refers to the chemical entity formed by theinteraction of water and a compound, including, for example,hemi-hydrates, monohydrates, dihydrates, trihydrates, etc.

As used herein, the term “polymorph” or “polymorphic form” refers to acrystalline form of a compound. Different polymorphs may have differentphysical properties such as, for example, melting temperatures, heats offusion, solubilities, dissolution rates, and/or vibrational spectra as aresult of the arrangement or conformation of the molecules or ions inthe crystal lattice. The differences in physical properties exhibited bypolymorphs may affect pharmaceutical parameters, such as storagestability, compressibility, density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph), mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph), or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of a crystallineform may be important in processing; for example, one polymorph might bemore likely to form solvates or might be difficult to filter and washfree of impurities (e.g., particle shape and size distribution might bedifferent between polymorphs).

As used herein, the term “subject” refers to an animal, such as amammal, bird, or fish. In some embodiments, the subject is a mammal.Mammals include, for example, mice, rats, dogs, cats, pigs, sheep,horses, cows and humans. In some embodiments, the subject is a human,for example a human that has been or will be the object of treatment,observation or experiment. The formulations, tablets, and methodsdescribed herein can be useful in both human therapy and veterinaryapplications.

As used herein, the term “therapeutic” refers to the ability to modulatethe cardiac sarcomere. As used herein, “modulation” refers to a changein activity as a direct or indirect response to the presence of achemical entity as described herein, relative to the activity of in theabsence of the chemical entity. The change may be an increase inactivity or a decrease in activity, and may be due to the directinteraction of the chemical entity with the a target or due to theinteraction of the chemical entity with one or more other factors thatin turn affect the target's activity. For example, the presence of thechemical entity may, for example, increase or decrease the targetactivity by directly binding to the target, by causing (directly orindirectly) another factor to increase or decrease the target activity,or by (directly or indirectly) increasing or decreasing the amount oftarget present in the cell or organism.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound disclosed and/or described herein that issufficient to affect treatment, as defined herein, when administered toa subject in need of such treatment. A therapeutically effective amountof a compound may be an amount sufficient to treat a disease responsiveto modulation of the cardiac sarcomere. The therapeutically effectiveamount will vary depending upon, for example, the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the particular compound, the dosing regimen tobe followed, timing of administration, the manner of administration, allof which can readily be determined by one of ordinary skill in the art.The therapeutically effective amount may be ascertained experimentally,for example by assaying blood concentration of the chemical entity, ortheoretically, by calculating bioavailability.

“Treatment” (and related terms, such as “treat”, “treated”, “treating”)includes one or more of: preventing a disease or disorder (i.e., causingthe clinical symptoms of the disease or disorder not to develop);inhibiting a disease or disorder; slowing or arresting the developmentof clinical symptoms of a disease or disorder; and/or relieving adisease or disorder (i.e., causing relief from or regression of clinicalsymptoms). The term encompasses situations where the disease or disorderis already being experienced by a subject, as well as situations wherethe disease or disorder is not currently being experienced but isexpected to arise. The term covers both complete and partial reductionor prevention of the condition or disorder, and complete or partialreduction of clinical symptoms of a disease or disorder. Thus, compoundsdescribed and/or disclosed herein may prevent an existing disease ordisorder from worsening, assist in the management of the disease ordisorder, or reduce or eliminate the disease or disorder. When used in aprophylactic manner, the compounds disclosed and/or described herein mayprevent a disease or disorder from developing or lessen the extent of adisease or disorder that may develop.

“ATPase” refers to an enzyme that hydrolyzes ATP. ATPases includeproteins comprising molecular motors such as the myosins.

The compound depicted herein may be present as a salt even if a salt isnot depicted, and it is understood that the formulations, tablets, andmethods provided herein embrace all salts and solvates of the compounddepicted here, as well as the non-salt and non-solvate form of thecompound, as is well understood by the skilled artisan. In someembodiments, the salts of the compound provided herein arepharmaceutically acceptable salts.

Formulations

Provided herein is a formulation comprising: (i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) a filler; (iii) a binder; (iv) a disintegrant; (v) asurfactant; and (vi) a lubricant.

In some embodiments, provided is a formulation comprising: (i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) a filler; (iii) a binder; (iv) a disintegrant; (v) a surfactant;and (vi) a lubricant.

In some embodiments, the filler is selected from the group consisting ofpowdered cellulose, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, kaolin, corn starch, maize starch, starchderivatives, pregelatinized starch, calcium phosphate, calcium hydrogenphosphate, dicalcium phosphate, tricalcium phosphate, compressiblesugar, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, lactitol,lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose,raffinose, dextrates, trehalose, maltodextrines. and mixtures of any ofthe foregoing.

In some embodiments, the binder is selected from the group consisting ofarabic gum, acacia gum, alginate, alginic acid, corn starch,copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate,hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hypromellose, lactose, polyvinyl alcohol, povidone,polyethylene oxide, polyacrylates, potato starch, pregelatinized starch,sodium alginate, sodium starch, sodium carboxy methyl cellulose, starch,and mixtures of any of the foregoing.

In some embodiments, the disintegrant is selected from the groupconsisting of alginic acid, croscarmellose sodium, cellulose,carboxymethylcellulose calcium, carboxymethylcellulose sodium,microcrystalline cellulose, crospovidone, sodium starch glycolate,low-substituted hydroxypropyl cellulose, polacrillin potassium,pregelatinized starch, partially hydrolyzed starch, sodium carboxymethylstarch, starch, sodium alginate, sodium carboxy methyl cellulose, andmixtures of any of the foregoing.

In some embodiments, the surfactant is selected from the groupconsisting of cetylpyridine chloride, heptadecaethylene oxycetanol,lecithins, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10,octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span80, Span 85, polysorbates, polysorbate 20, polysorbate 21, polysorbate40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80,sodium salts of fatty alcohol sulfates, sodium lauryl sulfate, sodiumsalts of sulfosuccinates, sodium dioctylsulfosuccinate, partial estersof fatty acids with alcohols, glycerine monostearate, glycerylmonooleate, ethers of fatty alcohols with polyoxyethylene, esters offatty acids with polyoxyethylene, copolymers of ethylenoxide andpropylenoxide (Pluronic®), benzalkonium chloride, ethoxylatedtriglycerides, and mixtures of any of the foregoing.

In some embodiments, the lubricant is selected from the group consistingof hydrogenated castor oil, magnesium stearate, glyceryl monostearate,calcium stearate, glyceryl behenate, glycerol distearate, glyceryldipalmitostearate, behenoyl polyoxyl-8 glycerides, sodium stearylfumarate, stearic acid, talc, zinc stearate, mineral oil, polyethyleneglycol, polaxamer, sodium lauryl sulfate, and mixtures of any of theforegoing.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 80% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 15% by weight to about 90% by weight of the filler;(iii) about 0.1% by weight to about 10% by weight of the binder; (iv)about 1% by weight to about 10% by weight of the disintegrant; (v) about0.1% by weight to about 10% by weight of the surfactant; and (vi) about0.1% by weight to about 10% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 80% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 15% by weight to about 90% by weight of the filler; (iii)about 0.1% by weight to about 10% by weight of the binder; (iv) about 1%by weight to about 10% by weight of the disintegrant; (v) about 0.1% byweight to about 10% by weight of the surfactant; and (vi) about 0.1% byweight to about 10% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 50% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 40% by weight to about 80% by weight of the filler;(iii) about 0.5% by weight to about 5% by weight of the binder; (iv)about 2% by weight to about 8% by weight of the disintegrant; (v) about0.5% by weight to about 5% by weight of the surfactant; and (vi) about0.5% by weight to about 5% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 50% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 40% by weight to about 80% by weight of the filler; (iii)about 0.5% by weight to about 5% by weight of the binder; (iv) about 2%by weight to about 8% by weight of the disintegrant; (v) about 0.5% byweight to about 5% by weight of the surfactant; and (vi) about 0.5% byweight to about 5% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 10% by weightto about 30% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 60% by weight to about 80% by weight of the filler;(iii) about 1% by weight to about 3% by weight of the binder; (iv) about4% by weight to about 6% by weight of the disintegrant; (v) about 1% byweight to about 3% by weight of the surfactant; and (vi) about 0.5% byweight to about 1.5% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 10% by weightto about 30% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 60% by weight to about 80% by weight of the filler; (iii)about 1% by weight to about 3% by weight of the binder; (iv) about 4% byweight to about 6% by weight of the disintegrant; (v) about 1% by weightto about 3% by weight of the surfactant; and (vi) about 0.5% by weightto about 1.5% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 20% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 70% by weight of the filler; (iii) about 2% byweight of the binder; (iv) about 5% by weight of the disintegrant; (v)about 2% by weight of the surfactant; and (vi) about 1% by weight of thelubricant.

In some embodiments, the formulation comprises: (i) about 20% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 70% by weight of the filler; (iii) about 2% by weight of thebinder; (iv) about 5% by weight of the disintegrant; (v) about 2% byweight of the surfactant; and (vi) about 1% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 10% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 70% by weight to about 90% by weight of the filler;(iii) about 1% by weight to about 3% by weight of the binder; (iv) about4% by weight to about 6% by weight of the disintegrant; (v) about 1% byweight to about 3% by weight of the surfactant; and (vi) about 0.5% byweight to about 1.5% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 10% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 70% by weight to about 90% by weight of the filler; (iii)about 1% by weight to about 3% by weight of the binder; (iv) about 4% byweight to about 6% by weight of the disintegrant; (v) about 1% by weightto about 3% by weight of the surfactant; and (vi) about 0.5% by weightto about 1.5% by weight of the lubricant.

In some embodiments, the formulation comprises:(i) about 5% by weight ofthe(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 85% by weight of the filler; (iii) about 2% byweight of the binder; (iv) about 5% by weight of the disintegrant; (v)about 2% by weight of the surfactant; and (vi) about 1% by weight of thelubricant.

In some embodiments, the formulation comprises: (i) about 5% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 85% by weight of the filler; (iii) about 2% by weight of thebinder; (iv) about 5% by weight of the disintegrant; (v) about 2% byweight of the surfactant; and (vi) about 1% by weight of the lubricant.

In some embodiments, the formulation comprises: (i) about 10% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii) about 80% by weight of the filler; (iii) about 2% byweight of the binder; (iv) about 5% by weight of the disintegrant; (v)about 2% by weight of the surfactant; and (vi) about 1% by weight of thelubricant.

In some embodiments, the formulation comprises: (i) about 10% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii) about 80% by weight of the filler; (iii) about 2% by weight of thebinder; (iv) about 5% by weight of the disintegrant; (v) about 2% byweight of the surfactant; and (vi) about 1% by weight of the lubricant.

In some embodiments, the filler comprises mannitol. In some embodiments,the filler comprises microcrystalline cellulose. In some embodiments,the filler consists of mannitol and microcrystalline cellulose. In someembodiments, the binder is hydroxypropyl cellulose. In some embodiments,the disintegrant is croscarmellose sodium. In some embodiments, thesurfactant is sodium lauryl sulfate. In some embodiments, the lubricantis magnesium stearate.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 50% by weight of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 10% by weight to about 60% by weight of mannitol;(ii-2) about 5% by weight to about 45% by weight of microcrystallinecellulose; (iii) about 0.1% by weight to about 10% by weight ofhydroxypropyl cellulose; (iv) about 1% by weight to about 10% by weightof croscarmellose sodium; (v) about 0.1% by weight to about 10% byweight of sodium lauryl sulfate; and (vi) about 0.1% by weight to about10% by weight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 50% by weight of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 10% by weight to about 60% by weight of mannitol; (ii-2)about 5% by weight to about 45% by weight of microcrystalline cellulose;(iii) about 0.1% by weight to about 10% by weight of hydroxypropylcellulose; (iv) about 1% by weight to about 10% by weight ofcroscarmellose sodium; (v) about 0.1% by weight to about 10% by weightof sodium lauryl sulfate; and (vi) about 0.1% by weight to about 10% byweight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 10% by weightto about 30% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 40% by weight to about 50% by weight of mannitol;(ii-2) about 20% by weight to about 30% by weight of microcrystallinecellulose; (iii) about 1% by weight to about 3% by weight ofhydroxypropyl cellulose; (iv) about 4% by weight to about 6% by weightof croscarmellose sodium; (v) about 1% by weight to about 3% by weightof sodium lauryl sulfate; and (vi) about 0.5% by weight to about 1.5% byweight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 10% by weightto about 30% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 40% by weight to about 50% by weight of mannitol; (ii-2)about 20% by weight to about 30% by weight of microcrystallinecellulose; (iii) about 1% by weight to about 3% by weight ofhydroxypropyl cellulose; (iv) about 4% by weight to about 6% by weightof croscarmellose sodium; (v) about 1% by weight to about 3% by weightof sodium lauryl sulfate; and (vi) about 0.5% by weight to about 1.5% byweight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 10% by weight of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 50% by weight to about 60% by weight of mannitol;(ii-2) about 25% by weight to about 35% by weight of microcrystallinecellulose; (iii) about 1% by weight to about 3% by weight ofhydroxypropyl cellulose; (iv) about 4% by weight to about 6% by weightof croscarmellose sodium; (v) about 1% by weight to about 3% by weightof sodium lauryl sulfate; and (vi) about 0.5% by weight to about 1.5% byweight of the magnesium stearate.

In some embodiments, the formulation comprises: (i) about 1% by weightto about 10% by weight of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 50% by weight to about 60% by weight of mannitol; (ii-2)about 25% by weight to about 35% by weight of microcrystallinecellulose; (iii) about 1% by weight to about 3% by weight ofhydroxypropyl cellulose; (iv) about 4% by weight to about 6% by weightof croscarmellose sodium; (v) about 1% by weight to about 3% by weightof sodium lauryl sulfate; and (vi) about 0.5% by weight to about 1.5% byweight of the magnesium stearate.

In some embodiments, the formulation comprises: (i) about 20% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 44% by weight of mannitol; (ii-2) about 26% byweight of microcrystalline cellulose; (iii) about 2% by weight ofhydroxypropyl cellulose; (iv) about 5% by weight of croscarmellosesodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about1% by weight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 20% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 44% by weight of mannitol; (ii-2) about 26% by weight ofmicrocrystalline cellulose; (iii) about 2% by weight of hydroxypropylcellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight ofmagnesium stearate.

In some embodiments, the formulation comprises: (i) about 10% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 50% by weight of mannitol; (ii-2) about 30% byweight of microcrystalline cellulose; (iii) about 2% by weight ofhydroxypropyl cellulose; (iv) about 5% by weight of croscarmellosesodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about1% by weight of magnesium stearate.

In some embodiments, the formulation comprises: (i) about 10% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 50% by weight of mannitol; (ii-2) about 30% by weight ofmicrocrystalline cellulose; (iii) about 2% by weight of hydroxypropylcellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight ofmagnesium stearate.

In some embodiments, the formulation comprises: (i) about 5% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (ii-1) about 54% by weight of mannitol; (ii-2) about 31% byweight of microcrystalline cellulose; (iii) about 2% by weight ofhydroxypropyl cellulose; (iv) about 5% by weight of croscarmellosesodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about1% by weight of the magnesium stearate.

In some embodiments, the formulation comprises: (i) about 5% by weightof the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(ii-1) about 54% by weight of mannitol; (ii-2) about 31% by weight ofmicrocrystalline cellulose; (iii) about 2% by weight of hydroxypropylcellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight ofthe magnesium stearate.

Administration of the formulation disclosed herein can be via anyaccepted mode of administration for solid and semi-solid formulationsincluding, but not limited to, oral, sublingual, subcutaneous,parenteral, intranasal, topical, transdermal, intraperitoneal,intramuscular, intrapulmonary, vaginal, rectal, or intraocularadministration. In some embodiments, the formulation is for oral orsublingual administration. In some embodiments, the formulation is fororal administration.

In some embodiments, the formulation is for administration once daily.In some embodiments, the formulation is for administration twice daily.In some embodiments, the formulation is for administration three timesdaily. In some embodiments, the formulation is for administration fourtimes daily. In some embodiments, the formulation is for administrationfive times daily.

In some embodiments, the formulation takes the form of a pill, acapsule, or a tablet. In some embodiments, the formulation is a tablet.

Tablets

Provided herein is a tablet comprising: (i) a core having a total coreweight comprising: (a) an intra-granular component comprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) an intra-granular filler; (a-iii) an intra-granularbinder; (a-iv) an intra-granular disintegrant; and (a-v) anintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) an extra-granular filler; (b-ii) an extra-granulardisintegrant; and (b-iii) an extra-granular lubricant; and optionally(ii) a coating layer comprising a coating agent.

In some embodiments, provided is a tablet comprising: (i) a core havinga total core weight comprising: (a) an intra-granular componentcomprising: (a-i)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) an intra-granular filler; (a-iii) an intra-granular binder;(a-iv) an intra-granular disintegrant; and (a-v) an intra-granularsurfactant; and (b) an extra-granular component comprising: (b-i) anextra-granular filler; (b-ii) an extra-granular disintegrant; and(b-iii) an extra-granular lubricant; and optionally (ii) a coating layercomprising a coating agent.

In some embodiments, the intra-granular filler is selected from thegroup consisting of powdered cellulose, microcrystalline cellulose,silicified microcrystalline cellulose, kaolin, corn starch, maizestarch, starch derivatives, pregelatinized starch, calcium phosphate,calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate,compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol,xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose,fructose, saccharose, raffinose, dextrates, trehalose, maitodextrines,and mixtures of any of the foregoing.

In some embodiments, the intra-granular binder is selected from thegroup consisting of arabic gum, acacia gum, alginate, alginic acid, cornstarch, copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate,hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hypromellose, lactose, polyvinyl alcohol, povidone,polyethylene oxide, polyacrylates, potato starch, pregelatinized starch,sodium alginate, sodium starch, sodium carboxy methyl cellulose, starch,and mixtures of any of the foregoing.

In some embodiments, the intra-granular disintegrant is selected fromthe group consisting of alginic acid, croscarmellose sodium, cellulose,carboxymethylcellulose calcium, carboxymethylcellulose sodium,microcrystalline cellulose, crospovidone, sodium starch glycolate,low-substituted hydroxypropyl cellulose, polacrillin potassium,pregelatinized starch, partially hydrolyzed starch, sodium carboxymethylstarch, starch, sodium alginate, sodium carboxy methyl cellulose, andmixtures of any of the foregoing.

In some embodiments, the intra-granular surfactant is selected from thegroup consisting of cetylpyridine chloride, heptadecaethyleneoxycetanol, lecithins, polyoxyethylene stearate, nonoxynol 9, nonoxynol10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60,Span 80, Span 85, polysorbates, polysorbate 20, polysorbate 21,polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65,polysorbate 80, sodium salts of fatty alcohol sulfates, sodium laurylsulfate, sodium salts of sulfosuccinates, sodium dioctylsulfosuccinate,partial esters of fatty acids with alcohols, glycerine monostearate,glyceryl monooleate, ethers of fatty alcohols with polyoxyethylene,esters of fatty acids with polyoxyethylene, copolymers of ethylenoxideand propylenoxide (Pluronic®), benzalkonium chloride, ethoxylatedtriglycerides, and mixtures of any of the foregoing.

In some embodiments, the extra-granular filler is selected from thegroup consisting of powdered cellulose, microcrystalline cellulose,silicified microcrystalline cellulose, kaolin, corn starch, maizestarch, starch derivatives, pregelatinized starch, calcium phosphate,calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate,compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol,xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose,fructose, saccharose, raffinose, dextrates, trehalose, maltodextrines,and mixtures of any of the foregoing.

In some embodiments, the extra-granular disintegrant is selected fromthe group consisting of alginic acid, croscarmellose sodium, cellulose,carboxymethylcellulose calcium, carboxymethylcellulose sodium,microcrystalline cellulose, crospovidone, sodium starch glycolate,low-substituted hydroxypropyl cellulose, polacrillin potassium,pregelatinized starch, partially hydrolyzed starch, sodium carboxymethylstarch, starch, sodium alginate, sodium carboxy methyl cellulose, andmixtures of any of the foregoing.

In some embodiments, the extra-granular lubricant is selected from thegroup consisting of hydrogenated castor oil, magnesium stearate,glyceryl monostearate, calcium stearate, glyceryl behenate, glyceroldistearate, glyceryl dipalmitostearate, behenoyl polyoxyl-8 glycerides,sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil,polyethylene glycol, polaxamer, sodium laurvl sulfate, and mixtures ofany of the foregoing.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 80% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 10% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 0.1% to about 10% of the total coreweight of the intra-granular binder; (a-iv) about 0.1% to about 5% ofthe total core weight of the intra-granular disintegrant; and (a-v)about 0.1% to about 5% of the total core weight of the intra-granularsurfactant; and (b) an extra-granular component comprising: (b-i) about5% to about 15% of the total core weight of the extra-granular filler;(b-ii) about 0.1% to about 5% of the total core weight of theextra-granular disintegrant; and (b-iii) about 0.1% to about 5% of thetotal core weight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 80% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 10% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 0.1% to about 10% of the total coreweight of the intra-granular binder; (a-iv) about 0.1% to about 5% ofthe total core weight of the intra-granular disintegrant; and (a-v)about 0.1% to about 5% of the total core weight of the intra-granularsurfactant; and (b) an extra-granular component comprising: (b-i) about5% to about 15% of the total core weight of the extra-granular filler;(b-ii) about 0.1% to about 5% of the total core weight of theextra-granular disintegrant; and (b-iii) about 0.1% to about 5% of thetotal core weight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 50% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 40% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 5% of the total coreweight of the intra-granular binder; (a-iv) about 1% to about 5% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 5% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the extra-granular filler; (b-ii) about1% to about 5% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 2% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 50% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 40% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 5% of the total coreweight of the intra-granular binder; (a-iv) about 1% to about 5% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 5% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the extra-granular filler; (b-ii) about1% to about 5% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 2% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% to about 30% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 50% to about 70% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 3% of the total coreweight of the intra-granular binder; (a-iv) about 2% to about 4% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 3% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the an extra-granular filler; (b-ii)about 1% to about 3% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 1.5% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% to about 30% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 50% to about 70% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 3% of the total coreweight of the intra-granular binder; (a-iv) about 2% to about 4% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 3% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the an extra-granular filler; (b-ii)about 1% to about 3% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 1.5% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 60% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 3% of the total coreweight of the intra-granular binder; (a-iv) about 2% to about 4% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 3% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the an extra-granular filler; (b-ii)about 1% to about 3% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 1.5% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 60% to about 80% of the total core weight of theintra-granular filler; (a-iii) about 1% to about 3% of the total coreweight of the intra-granular binder; (a-iv) about 2% to about 4% of thetotal core weight of the intra-granular disintegrant; and (a-v) about 1%to about 3% of the total core weight of the intra-granular surfactant;and (b) an extra-granular component comprising: (b-i) about 5% to about15% of the total core weight of the an extra-granular filler; (b-ii)about 1% to about 3% of the total core weight of the extra-granulardisintegrant; and (b-iii) about 0.1% to about 1.5% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 5% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 74% of the total core weight of the intra-granularfiller; (a-iii) about 2% of the total core weight of the intra-granularbinder; (a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 5% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 74% of the total core weight of the intra-granular filler;(a-iii) about 2% of the total core weight of the intra-granular binder;(a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 69% of the total core weight of the intra-granularfiller; (a-iii) about 2% of the total core weight of the intra-granularbinder; (a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 69% of the total core weight of the intra-granular filler;(a-iii) about 2% of the total core weight of the intra-granular binder;(a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii) about 59% of the total core weight of the intra-granularfiller; (a-iii) about 2% of the total core weight of the intra-granularbinder; (a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii) about 59% of the total core weight of the intra-granular filler;(a-iii) about 2% of the total core weight of the intra-granular binder;(a-iv) about 3% of the total core weight of the intra-granulardisintegrant; and (a-v) about 2% of the total core weight of theintra-granular surfactant; and (b) an extra-granular componentcomprising: (b-i) about 11% of the total core weight of the anextra-granular filler; (b-ii) about 2% of the total core weight of theextra-granular disintegrant; and (b-iii) about 1% of the total coreweight of the extra-granular lubricant.

In some embodiments, the intra-granular filler comprises mannitol. Insome embodiments, the intra-granular filler comprises microcrystallinecellulose. In some embodiments, the intra-granular filler consists ofmannitol and microcrystalline cellulose. In some embodiments, theintra-granular binder is hydroxypropyl cellulose. In some embodiments,the intra-granular disintegrant is croscarmellose sodium. In someembodiments, the intra-granular surfactant is sodium lauryl sulfate. Insome embodiments, the extra-granular filler is microcrystallinecellulose. In some embodiments, the extra-granular disintegrant iscroscarmellose sodium. In some embodiments, the extra-granular lubricantis magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 50% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 40% to about 60% of the total core weight ofmannitol; (a-ii-2) about 10% to about 30% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 5% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 1% to about 5% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 5% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 5% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 2% of the total core weight of extra-granularlubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 50% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 40% to about 60% of the total core weight ofmannitol; (a-ii-2) about 10% to about 30% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 5% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 1% to about 5% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 5% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 5% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 2% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% to about 50% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 40% to about 60% of the total core weight of mannitol;(a-ii-2) about 10% to about 30% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 5% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 1% to about 5% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 5% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 5% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 2% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% to about 30% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 40% to about 50% of the total core weight ofmannitol; (a-ii-2) about 10% to about 20% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of extra-granularlubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% to about 30% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 40% to about 50% of the total core weight ofmannitol; (a-ii-2) about 10% to about 20% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% to about 30% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 40% to about 50% of the total core weight of mannitol;(a-ii-2) about 10% to about 20% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% by weight to about 10% of the total coreweight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 50% to about 60% of the total core weight ofmannitol; (a-ii-2) about 15% to about 25% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of extra-granularlubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% by weight to about 10% of the total coreweight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 50% to about 60% of the total core weight ofmannitol; (a-ii-2) about 15% to about 25% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 1% by weight to about 10% of the total coreweight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 50% to about 60% of the total core weight of mannitol;(a-ii-2) about 15% to about 25% of the total core weight ofmicrocrystalline cellulose; (a-iii) about 1% to about 3% of the totalcore weight of hydroxypropyl cellulose; (a-iv) about 2% to about 4% ofthe total core weight of croscarmellose sodium; and (a-v) about 1% toabout 3% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 5% to about 15% of thetotal core weight of microcrystalline cellulose; (b-ii) about 1% toabout 3% of the total core weight of croscarmellose sodium; and (b-iii)about 0.1% to about 1.5% of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 44% of the total core weight of mannitol;(a-ii-2) about 15% of the total core weight of microcrystallinecellulose; (a-iii) about 2% of the total core weight of hydroxypropylcellulose; (a-iv) about 3% of the total core weight of croscarmellosesodium; and (a-v) about 2% of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11%of the total core weight of microcrystalline cellulose; (b-ii) about 2%of the total core weight of croscarmellose sodium; and (b-iii) about 1%of the total core weight of extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 44% of the total core weight of mannitol;(a-ii-2) about 15% of the total core weight of microcrystallinecellulose; (a-iii) about 2% of the total core weight of hydroxypropylcellulose; (a-iv) about 3% of the total core weight of croscarmellosesodium; and (a-v) about 2% of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11%of the total core weight of microcrystalline cellulose; (b-ii) about 2%of the total core weight of croscarmellose sodium; and (b-iii) about 1%of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 44% of the total core weight of mannitol; (a-ii-2) about15% of the total core weight of microcrystalline cellulose; (a-iii)about 2% of the total core weight of hydroxypropyl cellulose; (a-iv)about 3% of the total core weight of croscarmellose sodium; and (a-v)about 2% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 11% of the total coreweight of microcrystalline cellulose; (b-ii) about 2% of the total coreweight of croscarmellose sodium; and (b-iii) about 1% of the total coreweight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 50% of the total core weight of mannitol;(a-ii-2) about 19% of the total core weight of microcrystallinecellulose; (a-iii) about 2% of the total core weight of hydroxypropylcellulose; (a-iv) about 3% of the total core weight of croscarmellosesodium; and (a-v) about 2% of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11%of the total core weight of microcrystalline cellulose; (b-ii) about 2%of the total core weight of croscarmellose sodium; and (b-iii) about 1%of the total core weight of extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 50% of the total core weight of mannitol;(a-ii-2) about 19% of the total core weight of microcrystallinecellulose; (a-iii) about 2% of the total core weight of hydroxypropylcellulose; (a-iv) about 3% of the total core weight of croscarmellosesodium; and (a-v) about 2% of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11%of the total core weight of microcrystalline cellulose; (b-ii) about 2%of the total core weight of croscarmellose sodium; and (b-iii) about 1%of the total core weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 10% of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 50% of the total core weight of mannitol; (a-ii-2) about19% of the total core weight of microcrystalline cellulose; (a-iii)about 2% of the total core weight of hydroxypropyl cellulose; (a-iv)about 3% of the total core weight of croscarmellose sodium; and (a-v)about 2% of the total core weight of sodium lauryl sulfate; and (b) anextra-granular component comprising: (b-i) about 11% of the total coreweight of microcrystalline cellulose; (b-ii) about 2% of the total coreweight of croscarmellose sodium; and (b-iii) about 1% of the total coreweight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 5% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% byweight of microcrystalline cellulose; (a-iii) about 2% by weight ofhydroxypropyl cellulose; (a-iv) about 3% by weight of croscarmellosesodium; and (a-v) about 2% by weight of sodium lauryl sulfate; and (b)an extra-granular component comprising: (b-i) about 11% by weight ofmicrocrystalline cellulose; (b-ii) about 2% by weight of croscarmellosesodium; and (b-iii) about 1% by weight of extra-granular lubricant.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 5% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% byweight of microcrystalline cellulose; (a-iii) about 2% by weight ofhydroxypropyl cellulose; (a-iv) about 3% by weight of croscarmellosesodium; and (a-v) about 2% by weight of sodium lauryl sulfate; and (b)an extra-granular component comprising: (b-i) about 11% by weight ofmicrocrystalline cellulose; (b-ii) about 2% by weight of croscarmellosesodium; and (b-iii) about 1% by weight of magnesium stearate.

In some embodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 5% by weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% by weightof microcrystalline cellulose; (a-iii) about 2% by weight ofhydroxypropyl cellulose; (a-iv) about 3% by weight of croscarmellosesodium; and (a-v) about 2% by weight of sodium lauryl sulfate; and (b)an extra-granular component comprising: (b-i) about 11% by weight ofmicrocrystalline cellulose; (b-ii) about 2% by weight of croscarmellosesodium; and (b-iii) about 1% by weight of magnesium stearate.

In some embodiments, the tablet comprises a coating layer comprising acoating agent. In some embodiments, the coating agent is selected fromthe group consisting of Opadry QX White 21A180025, Opadry I, and OpadryII. In some embodiments, the coating agent is Opadry QX White 21A180025.In some embodiments, the tablet comprises about 0.5% to about 10% of thetotal core weight of coating agent. In some embodiments, the tabletcomprises about 1% to about 5% of the total core weight of coatingagent. In some embodiments, the tablet comprises about 2% to about 4% ofthe total core weight of coating agent. In some embodiments, the tabletcomprises about 3% of the total core weight of coating agent. In someembodiments, the tablet comprises about 0.5% to about 10% of the totalcore weight of Opadry QX White 21A180025. In some embodiments, thetablet comprises about 1% to about 5% of the total core weight of OpadryQX White 21A180025. In some embodiments, the tablet comprises about 2%to about 4% of the total core weight of Opadry QX White 21A180025. Insome embodiments, the tablet comprises about 3% of the total core weightof Opadry QX White 21A180025.

In some embodiments, the total core weight is about 50 mg. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 2.5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 27 mg of the total core weight of mannitol;(a-ii-2) about 10 mg of the total core weight of microcrystallinecellulose; (a-iii) about 1 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 1.5 mg of the total core weight ofcroscarmellose sodium; and (a-v) about 1 mg of the total core weight ofsodium lauryl sulfate; and (b) an extra-granular component comprising:(b-i) about 5.5 mg of the total core weight of microcrystallinecellulose; (b-ii) about 1 mg of the total core weight of croscarmellosesodium; and (b-iii) about 0.5 mg of the total core weight ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 2.5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 27 mg of the total core weight of mannitol;(a-ii-2) about 10 mg of the total core weight of microcrystallinecellulose; (a-iii) about 1 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 1.5 mg of the total core weight ofcroscarmellose sodium; and (a-v) about 1 mg of the total core weight ofsodium lauryl sulfate; and (b) an extra-granular component comprising:(b-i) about 5.5 mg of the total core weight of microcrystallinecellulose; (b-ii) about 1 mg of the total core weight of croscarmellosesodium; and (b-iii) about 0.5 mg of the total core weight of magnesiumstearate. In some embodiments, the core comprises: (a) an intra-granularcomponent comprising: (a-i) about 2.5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 27 mg of the total core weight of mannitol; (a-ii-2)about 10 mg of the total core weight of microcrystalline cellulose;(a-iii) about 1 mg of the total core weight of hydroxypropyl cellulose;(a-iv) about 1.5 mg of the total core weight of croscarmellose sodium;and (a-v) about 1 mg of the total core weight of sodium lauryl sulfate;and (b) an extra-granular component comprising: (b-i) about 5.5 mg ofthe total core weight of microcrystalline cellulose; (b-ii) about 1 mgof the total core weight of croscarmellose sodium; and (b-iii) about 0.5mg of the total core weight of magnesium stearate. In some embodiments,the tablet comprises about 1.5 mg of coating agent. In some embodiments,the coating agent is Opadry QX White 21A180025.

In some embodiments, the total core weight is about 100 mg. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 44 mg of the total core weight of mannitol;(a-ii-2) about 15 mg of the total core weight of microcrystallinecellulose; (a-iii) about 2 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 3 mg of the total core weight of croscarmellosesodium; and (a-v) about 2 mg of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11mg of the total core weight of microcrystalline cellulose; (b-ii) about2 mg of the total core weight of croscarmellose sodium; and (b-iii)about 1 mg of the total core weight of extra-granular lubricant. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 44 mg of the total core weight of mannitol;(a-ii-2) about 15 mg of the total core weight of microcrystallinecellulose; (a-iii) about 2 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 3 mg of the total core weight of croscarmellosesodium; and (a-v) about 2 mg of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 11mg of the total core weight of microcrystalline cellulose; (b-ii) about2 mg of the total core weight of croscarmellose sodium; and (b-iii)about 1 mg of the total core weight of magnesium stearate. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 20 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 44 mg of the total core weight of mannitol; (a-ii-2)about 15 mg of the total core weight of microcrystalline cellulose;(a-iii) about 2 mg of the total core weight of hydroxypropyl cellulose;(a-iv) about 3 mg of the total core weight of croscarmellose sodium; and(a-v) about 2 mg of the total core weight of sodium lauryl sulfate; and(b) an extra-granular component comprising: (b-i) about 11 mg of thetotal core weight of microcrystalline cellulose; (b-ii) about 2 mg ofthe total core weight of croscarmellose sodium; and (b-iii) about 1 mgof the total core weight of magnesium stearate. In some embodiments, thecore comprises: (a) an intra-granular component comprising: (a-i) about5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 54 mg of mannitol; (a-ii-2) about 20 mg ofmicrocrystalline cellulose; (a-iii) about 2 mg of hydroxypropylcellulose; (a-iv) about 3 mg of croscarmellose sodium; and (a-v) about 2mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 11 mg of microcrystalline cellulose; (b-ii)about 2 mg of croscarmellose sodium; and (b-iii) about 1 mg ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 54 mg of mannitol; (a-ii-2) about 20 mg ofmicrocrystalline cellulose; (a-iii) about 2 mg of hydroxypropylcellulose; (a-iv) about 3 mg of croscarmellose sodium; and (a-v) about 2mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 11 mg of microcrystalline cellulose; (b-ii)about 2 mg of croscarmellose sodium; and (b-iii) about 1 mg of magnesiumstearate. In some embodiments, the core comprises: (a) an intra-granularcomponent comprising: (a-i) about 5 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 54 mg of mannitol; (a-ii-2) about 20 mg ofmicrocrystalline cellulose; (a-iii) about 2 mg of hydroxypropylcellulose; (a-iv) about 3 mg of croscarmellose sodium; and (a-v) about 2mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 11 mg of microcrystalline cellulose; (b-ii)about 2 mg of croscarmellose sodium; and (b-iii) about 1 mg of magnesiumstearate. In some embodiments, the tablet comprises about 3 mg ofcoating agent. In some embodiments, the coating agent is Opadry QX White21A180025.

In some embodiments, the total core weight is about 200 mg. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 40 mg of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 88 mg of the total core weight of mannitol;(a-ii-2) about 30 mg of the total core weight of microcrystallinecellulose; (a-iii) about 4 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 6 mg of the total core weight of croscarmellosesodium; and (a-v) about 4 mg of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 22mg of the total core weight of microcrystalline cellulose; (b-ii) about4 mg of the total core weight of croscarmellose sodium; and (b-iii)about 2 mg of the total core weight of extra-granular lubricant. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 40 mg of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 88 mg of the total core weight of mannitol;(a-ii-2) about 30 mg of the total core weight of microcrystallinecellulose; (a-iii) about 4 mg of the total core weight of hydroxypropylcellulose; (a-iv) about 6 mg of the total core weight of croscarmellosesodium; and (a-v) about 4 mg of the total core weight of sodium laurylsulfate; and (b) an extra-granular component comprising: (b-i) about 22mg of the total core weight of microcrystalline cellulose; (b-ii) about4 mg of the total core weight of croscarmellose sodium; and (b-iii)about 2 mg of the total core weight of magnesium stearate. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 40 mg of the total core weight of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 88 mg of the total core weight of mannitol; (a-ii-2)about 30 mg of the total core weight of microcrystalline cellulose;(a-iii) about 4 mg of the total core weight of hydroxypropyl cellulose;(a-iv) about 6 mg of the total core weight of croscarmellose sodium; and(a-v) about 4 mg of the total core weight of sodium lauryl sulfate; and(b) an extra-granular component comprising: (b-i) about 22 mg of thetotal core weight of microcrystalline cellulose; (b-ii) about 4 mg ofthe total core weight of croscarmellose sodium; and (b-iii) about 2 mgof the total core weight of magnesium stearate. In some embodiments, thecore comprises: (a) an intra-granular component comprising: (a-i) about10 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 108 mg of mannitol; (a-ii-2) about 40 mg ofmicrocrystalline cellulose; (a-iii) about 4 mg of hydroxypropylcellulose; (a-iv) about 6 mg of croscarmellose sodium; and (a-v) about 4mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 22 mg of microcrystalline cellulose; (b-ii)about 4 mg of croscarmellose sodium; and (b-iii) about 2 mg ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 10 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 108 mg of mannitol; (a-ii-2) about 40 mg ofmicrocrystalline cellulose; (a-iii) about 4 mg of hydroxypropylcellulose; (a-iv) about 6 mg of croscarmellose sodium; and (a-v) about 4mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 22 mg of microcrystalline cellulose; (b-ii)about 4 mg of croscarmellose sodium; and (b-iii) about 2 mg of magnesiumstearate. In some embodiments, the core comprises: (a) an intra-granularcomponent comprising: (a-i) about 10 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 108 mg of mannitol; (a-ii-2) about 40 mg ofmicrocrystalline cellulose; (a-iii) about 4 mg of hydroxypropylcellulose; (a-iv) about 6 mg of croscarmellose sodium; and (a-v) about 4mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 22 mg of microcrystalline cellulose; (b-ii)about 4 mg of croscarmellose sodium; and (b-iii) about 2 mg of magnesiumstearate. In some embodiments, the tablet comprises about 6 mg ofcoating agent. In some embodiments, the coating agent is Opadry QX White21A180025.

In some embodiments, the total core weight is about 70 mg. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 7 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 35 mg of mannitol; (a-ii-2) about 13.3 mg ofmicrocrystalline cellulose; (a-iii) about 1.4 mg of hydroxypropylcellulose; (a-iv) about 2.1 mg of croscarmellose sodium; and (a-v) about1.4 mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 7.7 mg of microcrystalline cellulose; (b-ii)about 1.4 mg of croscarmellose sodium; and (b-iii) about 0.7 mg ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 7 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 35 mg of mannitol; (a-ii-2) about 13.3 mg ofmicrocrystalline cellulose; (a-iii) about 1.4 mg of hydroxypropylcellulose; (a-iv) about 2.1 mg of croscarmellose sodium; and (a-v) about1.4 mg of magnesium stearate; and (b) an extra-granular componentcomprising: (b-i) about 7.7 mg of microcrystalline cellulose; (b-ii)about 1.4 mg of croscarmellose sodium; and (b-iii) about 0.7 mg ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 7 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 35 mg of mannitol; (a-ii-2) about 13.3 mg ofmicrocrystalline cellulose; (a-iii) about 1.4 mg of hydroxypropylcellulose; (a-iv) about 2.1 mg of croscarmellose sodium; and (a-v) about1.4 mg of magnesium stearate; and (b) an extra-granular componentcomprising: (b-i) about 7.7 mg of microcrystalline cellulose; (b-ii)about 1.4 mg of croscarmellose sodium; and (b-iii) about 0.7 mg ofextra-granular lubricant. In some embodiments, the tablet comprisesabout 2.1 mg of coating agent. In some embodiments, the coating agent isOpadry QX White 21A180025.

In some embodiments, the total core weight is about 400 mg. In someembodiments, the core comprises: (a) an intra-granular componentcomprising: (a-i) about 40 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 200 mg of mannitol; (a-ii-2) about 76 mg ofmicrocrystalline cellulose; (a-iii) about 8 mg of hydroxypropylcellulose; (a-iv) about 12 mg of croscarmellose sodium; and (a-v) about8 mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 44 mg of microcrystalline cellulose; (b-ii)about 8 mg of croscarmellose sodium; and (b-iii) about 4 mg ofextra-granular lubricant. In some embodiments, the core comprises: (a)an intra-granular component comprising: (a-i) about 40 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof; (a-ii-1) about 200 mg of mannitol; (a-ii-2) about 76 mg ofmicrocrystalline cellulose; (a-iii) about 8 mg of hydroxypropylcellulose; (a-iv) about 12 mg of croscarmellose sodium; and (a-v) about8 mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 44 mg of microcrystalline cellulose; (b-ii)about 8 mg of croscarmellose sodium; and (b-iii) about 4 mg of magnesiumstearate. In some embodiments, the core comprises: (a) an intra-granularcomponent comprising: (a-i) about 40 mg of the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide;(a-ii-1) about 200 mg of mannitol; (a-ii-2) about 76 mg ofmicrocrystalline cellulose; (a-iii) about 8 mg of hydroxypropylcellulose; (a-iv) about 12 mg of croscarmellose sodium; and (a-v) about8 mg of sodium lauryl sulfate; and (b) an extra-granular componentcomprising: (b-i) about 44 mg of microcrystalline cellulose; (b-ii)about 8 mg of croscarmellose sodium; and (b-iii) about 4 mg of magnesiumstearate. In some embodiments, the tablet comprises about 12 mg ofcoating agent. In some embodiments, the coating agent is Opadry QX White21A180025.

Fillers

Fillers are substances that can be added to components of apharmaceutical composition or formulation to increase bulk weight of thematerial to be formulated, e.g. tabletted, in order to achieve thedesired weight. Fillers include but are not limited to powderedcellulose, microcrystalline cellulose, silicified microcrystallinecellulose, kaolin, corn starch, maize starch, starch derivatives,pregelatinized starch, calcium phosphate, calcium hydrogen phosphate,dicalcium phosphate, tricaleium phosphate, compressible sugar, sugaralcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose,dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose,dextrates, trehalose, maltodextrines, and the like. In some embodiments,the filler is selected from the group consisting of powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose,kaolin, corn starch, maize starch, starch derivatives, pregelatinizedstarch, calcium phosphate, calcium hydrogen phosphate, dicalciumphosphate, tricalcium phosphate, compressible sugar, sugar alcohol,mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose,maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates,trehalose, maltodextrines, and mixtures of any of the foregoing. In someembodiments, the filler is selected from the group consisting ofmicrocrystalline cellulose, mannitol, and mixtures of any of theforegoing. In some embodiments, the filler comprises mannitol. In someembodiments, the filler comprises microcrystalline cellulose. In someembodiments, the filler comprises microcrystalline cellulose andmannitol.

Binders

Binders are substances that can be added to components of apharmaceutical composition or formulation to act as an adhesive to bindtogether powders, granules, and other dry ingredients comprised in thepharmaceutical composition or formulation and impart to thepharmaceutical composition or formulation the desired mechanicalstrength. Binders include, but are not limited to, arabic gum, acaciagum, alginate, alginic acid, corn starch, copolyvidone,polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethylcellulose,hydroxypropyl cellulose, carboxymethylcellulose, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, methylcellulose, hypromellose,lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates,potato starch, pregelatinized starch, sodium alginate, sodium starch,sodium carboxy methyl cellulose, starch, and the likes. In someembodiments, the binder is selected from the group consisting of arabicgum, acacia gum, alginate, alginic acid, corn starch, copolyvidone,polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethylcellulose,hydroxypropyl cellulose, carboxymethylcellulose, carboxymethylcellulose,calcium, carboxymethylcellulose sodium, methylcellulose, hypromellose,lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates,potato starch, pregelatinized starch, sodium alginate, sodium starch,sodium carboxy methyl cellulose, starch, and mixtures of any of theforegoing. In some embodiments, the binder is selected from the groupconsisting of hydroxyethylcellulose, hydroxypropyl cellulose,carboxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, methylcellulose, hypromellose, sodiumcarboxy methyl cellulose, and mixtures of any of the foregoing. In someembodiments, the binder is hydroxypropyl cellulose.

Disintegrants

Disintegrants are substances that can be added to components of apharmaceutical composition or formulation to aid their deaggregation.Disintegrants can be formulated to provide rapid breakage of solidpharmaceutical compositions or formulations when they come into contactwith moisture. Disintegrants include, but are not limited to, alginicacid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone,sodium starch glycolate, low-substituted hydroxypropyl cellulose,polacrillin potassium, pregelatinized starch, partially hydrolyzedstarch, sodium carboxymethyl starch, starch, sodium alginate, sodiumcarboxy methyl cellulose, and mixtures of any of the foregoing. In someembodiments, the disintegrant is selected from the group consisting ofalginic acid, croscarmellose sodium, cellulose, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, microcrystalline cellulose,crospovidone, sodium starch glycolate, low-substituted hydroxypropylcellulose, polacrillin potassium, pregelatinized starch, partiallyhydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate,sodium carboxy methyl cellulose, and mixtures of any of the foregoing.In some embodiments, the disintegrant is selected from the groupconsisting of croscarmellose sodium, cellulose, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, microcrystalline cellulose,low-substituted hydroxypropyl cellulose, and mixtures of any of theforegoing. In some embodiments, the disintegrant is croscarmellosesodium.

Surfactants

Surfactants are substances that can be added to components of apharmaceutical composition or formulation to lower the surface tensionbetween two liquids or between a solid and a liquid and increasesolubility. Surfactants include, but are not limited to, cetylpyridinechloride, heptadecaethylene oxycetanol, lecithins, polyoxyethylene,stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acidesters, Span 20, Span 40, Span 60, Span 80, Span $5, polysorbates,polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60,polysorbate 61, polysorbate 65, polysorbate 80, sodium salts of fattyalcohol sulfates, sodium lauryl sulfate, sodium salts ofsulfosuccinates, sodium dioctylsulfosuccinate, partial esters of fattyacids with alcohols, glycerine monostearate, glyceryl monooleate, ethersof fatty alcohols with polyoxyethylene, esters of fatty acids withpolyoxyethylene, copolymers of ethylenoxide and propylenoxide(Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and thelikes. In some embodiments, the surfactant is selected from the groupconsisting of sodium salts of fatty alcohol sulfates, sodium laurylsulfate, sodium dodecyl sulfates, and mixtures of any of the foregoing.In some embodiments, the surfactant is sodium lauryl sulfate.

Lubricants

Lubricants are substances that can be added to components of the presentcompositions to reduce sticking by a solid formulation to the equipmentused for production of a unit doss form. Lubricants include, but are notlimited to, hydrogenated castor oil, magnesium stearate, glycerylmonostearate, calcium stearate, glyceryl behenate, glycerol distearate.glyceryl dipalmitostearate, behenoyl polyoxyl-8 glycerides, sodiumstearyl fumarate, stearic acid, talc, zinc stearate, mineral oil,polyethylene glycol, polaxamer, sodium lauryl sulfate, and the likes. Insome embodiments, the lubricant is selected from the group consisting ofhydrogenated castor oil, magnesium stearate, calcium stearate, zincstearate, and mixtures of any of the foregoing. In some embodiments, thelubricant is magnesium stearate.

Coating Agents

Coating agents are substances that can be added as an outer layersurrounding components of a pharmaceutical composition or formulation.Surfactants include, but are not limited to, Opadry QX White 21A180025,Opadry I, Opadry II, and the like. In some embodiments, the coatingagent is selected from the group consisting of Opadry QX White21A180025, Opadry I, and Opadry II. In some embodiments, the coatingagent is Opadry QX White 21A180025.

Additional Agents

Pharmaceutical compositions or formulations intended for the preparationof oral dosage forms (such as tablets and capsules) may further containone or more agents selected from the group consisting of sweeteningagents, flavoring agents, coloring agents, and preserving agents inorder to provide pharmaceutically elegant and palatable preparations.

Processes

Also provided herein is a process for making a tablet described herein,wherein the process comprises: (1) preparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or a hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant; (2)milling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant to formthe intra-granular component; (3) blending the intra-granular componentwith the extra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant to form a final blend mixture; (4) compressingthe final blend mixture to form the core; (5) optionally coating thecore with the coating layer.

In some embodiments, preparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant comprisesa wet granulation step. In some embodiments, the wet granulation step isperformed with a high shear granulator. In some embodiments, the wetgranulation step is performed with a fluid bed granulator. In someembodiments, the wet granulation step is performed with a granulatordrum. In some embodiments, the wet granulation step further comprises awet milling step. In some embodiments, the wet milling step is performedwith a conical mill. In some embodiments, the wet milling step isperformed with a turbo mill or hammer mill. In some embodiments, thepreparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant furthercomprises drying the granules. In some embodiments, drying the granulesis performed in a fluid bed dryer. In some embodiments, drying thegranules is performed in a tray dryer. In some embodiments, drying thegranules is performed in a belt dryer. In some embodiments, drying thegranules is performed in a vacuum tray dryer. In some embodiments,drying the granules is performed in a rotary dryer.

In some embodiments, milling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant isperformed with a conical mill. In some embodiments, milling the granulescomprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant isperformed with a turbo mill or hammer mill.

In some embodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a V-blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in an octagonal blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a mass blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a double cone blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a vertical blender.

In some embodiments, compressing the final blend mixture to form thecore is performed with a rotary tablet press. In some embodiments,compressing the final blend mixture to form the core is performed with asingle punch tablet press.

In some embodiments, the process comprises coating the core with thecoating layer. In some embodiments, coating the core with the coatinglayer is performed using a conventional coating pan, such as aPelligrini pan, an immersion sword type pan, or an immersion tube typepan. In some embodiments, coating the core with the coating layer isperformed using a perforated coating pan, such as an Accela-Cota pan, ahi-coater, a dria coater, a Glatt pan-coating equipment, a Huttlinbutterfly pan, or a Dumoulin Coating equipment.

In some embodiments, provided is a process for making a tablet describedherein, wherein the process comprises: (1) preparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant; (2) milling thegranules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant to form theintra-granular component; (3) blending the intra-granular component withthe extra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant to form a final blend mixture; (4) compressingthe final blend mixture to form the core; (5) optionally coating thecore with the coating layer.

In some embodiments, preparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant comprises a wetgranulation step. In some embodiments, the wet granulation step isperformed with a high shear granulator. In some embodiments, the wetgranulation step is performed with a fluid bed granulator. In someembodiments, the wet granulation step is performed with a granulatordrum. In some embodiments, the wet granulation step further comprises awet milling step. In some embodiments, the wet milling step is performedwith a conical mill. In some embodiments, the wet milling step isperformed with a turbo mill or hammer mill. In some embodiments, thepreparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant further comprises dryingthe granules. In some embodiments, drying the granules is performed in afluid bed dryer. In some embodiments, drying the granules is performedin a tray dryer. In some embodiments, drying the granules is performedin a belt dryer. In some embodiments, drying the granules is performedin a vacuum tray dryer. In some embodiments, drying the granules isperformed in a rotary dryer.

In some embodiments, milling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant is performed with aconical mill. In some embodiments, milling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the intra-granular filler, the intra-granular binder, the intra-granulardisintegrant, and the intra-granular surfactant is performed with aturbo mill or hammer mill.

In some embodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a V-blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in an octagonal blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a mass blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a double cone blender. In someembodiments, blending the intra-granular component with theextra-granular filler, the extra-granular disintegrant, and theextra-granular lubricant is performed in a vertical blender.

In some embodiments, compressing the final blend mixture to form thecore is performed with a rotary tablet press. In some embodiments,compressing the final blend mixture to form the core is performed with asingle punch tablet press.

In some embodiments, the process comprises coating the core with thecoating layer. In some embodiments, coating the core with the coatinglayer is performed using a conventional coating pan, such as aPelligrini pan, an immersion sword type pan, or an immersion tube typepan. In some embodiments, coating the core with the coating layer isperformed using a perforated coating pan, such as an Accela-Cota pan, ahi-coater, a dria coater, a Glatt pan-coating equipment, a Huttlinbutterfly pan, or a Dumoulin Coating equipment.

Methods of Use

The formulation or tablet described and/or disclosed herein may be usedto treat or prevent a disease or condition in a subject.

Without being bound by theory,(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideis believed to act by inhibiting myosin. This inhibition potentiallydecreases the number of independent myosin heads interacting with actinfilaments reducing the amount of contraction. Reducing contraction ofcardiac muscle can be important for the treatment of heart diseases inwhich over-contraction is an issue. In some embodiments, provided aremethods of treating or preventing heart disease in a subject, comprisingadministering to the subject in need thereof a formulation or tablet asdescribed herein. In some embodiments, provided are methods of treatingor preventing heart disease in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of aformulation or tablet as described herein. In some embodiments, providedare methods of treating heart disease in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of a formulation or tablet as described herein. In someembodiments, provided are methods of treating an established ordiagnosed heart disease in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of aformulation or tablet as described herein. In some embodiments, providedare methods of preventing heart disease in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of a formulation or tablet as described herein.

Also provided herein is the use of a formulation or tablet as describedherein in the manufacture of a medicament for treatment of a heartdisease in a subject. In some aspects, provided is a formulation ortablet as described herein for use in a method of treatment of the humanor animal body by therapy. In some embodiments, provided herein is aformulation or tablet as described herein, for use in a method oftreatment of the human or animal body by therapy. In some embodiments,provided herein is a formulation or tablet as described herein, for usein treating or preventing heart disease. In some embodiments, providedherein is a formulation or tablet as described herein, for use intreating heart disease. In some embodiments, provided herein is aformulation or tablet as described herein, for use in treating anestablished or diagnosed heart disease. In other embodiments, providedherein is a formulation or tablet as described herein, for use inpreventing heart disease. In some embodiments, provided herein is aformulation or tablet as described herein, for use in treating a diseaseor condition associated with HCM. In some embodiments, provided hereinis a formulation or tablet as described herein, for use in treating adisease or condition associated with secondary left ventricular wallthickening. In some embodiments, provided herein is a formulation ortablet as described herein, for use in ameliorating a symptom associatedwith heart disease. In some embodiments, provided herein is aformulation or tablet as described herein, for use in reducing the riskof a symptom associated with heart disease. In some embodiments,provided herein is a formulation or tablet as described herein, for usein treating a disease or condition associated with small leftventricular cavity, cavity obliteration, hyperdynamic left ventricularcontraction, obstruction of blood flow out of the left ventricle,cardiac hypertrophy, small cardiac stroke volume, impaired relaxation ofthe left ventricle, high left ventricle filling pressure, myocardialischemia, or cardiac fibrosis. In some embodiments, provided herein is aformulation or tablet as described herein, for use in treating a diseaseor condition associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis. In some embodiments, provided herein is aformulation or tablet as described herein, for use in treating musculardystrophies. In some embodiments, provided herein is a formulation ortablet as described herein, for use in treating a glycogen storagedisease. In some embodiments, provided herein is a formulation or tabletas described herein, for use in modulating the cardiac sarcomere, suchas inhibiting the cardiac sarcomere. In some embodiments, providedherein is a formulation or tablet as described herein, for use inpotentiating cardiac myosin.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. Insome embodiments, the subject is a human. In some embodiments, thesubject has an established or diagnosed heart disease. In someembodiments, the subject has established or diagnosed hypertrophiccardiomyopathy (HCM). In some embodiments, the subject is at risk fordeveloping heart disease. In some embodiments, the subject has amutation that increases risk for heart disease. In some embodiments, thesubject has a mutation that increases risk for hypertrophiccardiomyopathy (HCM). In some embodiments, the mutation is a sarcomericmutation. In some embodiments, the mutation is a mutation in myosinheavy chain β (MHC-β), cardiac muscle troponin T (cTnT), tropomyosinalpha-1 chain (TPM1), myosin-binding protein C cardiac-type (MYBPC3),cardiac troponin I (cTnI), myosin essential light chain (ELC), titin(TTN), myosin regulatory light chain 2 ventricular/cardiac muscleisoform (MLC-2), cardiac muscle alpha actin, muscle LIM protein (MLP),or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).In some embodiments, the mutation is a mutation in MHC-β. In someembodiments, the subject has established or diagnosed hypertrophiccardiomyopathy without a confirmed genetic etiology.

In some embodiments, the subject has a high risk of progressivesymptoms. In some embodiments, the subject has a high risk of atrialfibrillation, ventricular tachyarrhythmias, stroke, and/or sudden death.In some embodiments, the subject has a reduced exercise capacity. Insome embodiments, the reduced exercise capacity is as compared to anage-matched control population. In some embodiments, the subject iseligible for surgical intervention or percutaneous ablation to treat theheart disease.

In some embodiments, the heart disease is hypertrophic cardiomyopathy(HCM). In some embodiments, the heart disease is obstructive HCM. Insome embodiments, the heart disease is nonobstructive HCM. In someembodiments, the HCM is associated with a sarcomeric mutation. In someembodiments, the HCM is associated with a non-sarcomeric mutation. Insome embodiments, the heart disease is obstructive or nonobstructive HCMcaused by sarcomeric and/or non-sarcomeric mutations. In someembodiments, the sarcomeric mutation is a mutation in a myosin heavychain β (MHC-β), cardiac muscle troponin T (cTnT), tropomyosin alpha-1chain (TPM1), myosin-binding protein C cardiac-type (MYBPC3), cardiactroponin I (cTnI), myosin essential light chain (ELC), titin (TTN),myosin regulatory light chain 2 ventricular/cardiac muscle isoform(MLC-2), cardiac muscle alpha actin, or muscle LIM protein (MLP). Insome embodiments, the sarcomeric mutation is a mutation in MHC-P. Insome embodiments, the non-sarcomeric mutation is a mutation in proteinkinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

In some embodiments, provided herein are methods of treating a diseaseor condition associated with HCM, comprising administering to thesubject in need thereof a formulation or a tablet as described herein.In some embodiments, the disease or condition is Fabry's Disease, DanonDisease, mitochondrial cardiomyopathies, or Noonan Syndrome.

Also provided herein is the use of a formulation or a tablet asdescribed herein in the manufacture of a medicament for treatment of adisease or condition associated with HCM.

In some embodiments, the heart disease is heart failure with preservedejection fraction (HFpEF). In some embodiments, the heart disease isdiastolic dysfunction. In some embodiments, the heart disease iscardiomyopathy. In some embodiments, the heart disease is primary orsecondary restrictive cardiomyopathy. In some embodiments, the heartdisease is condition or symptoms caused by coronary artery disease. Insome embodiments, the heart disease is myocardial infarction or anginapectoris. In some embodiments, the heart disease is left ventricularoutflow tract obstruction. In some embodiments, the heart disease ishypertensive heart disease. In some embodiments, the heart disease iscongenital heart disease. In some embodiments, the heart disease iscardiac ischemia and/or coronary heart disease. In some embodiments, theheart disease is diabetic heart disease. In other embodiments, the heartdisease is congestive heart failure. In some embodiments, the heartdisease is right heart failure. In other embodiments, the heart diseaseis cardiorenal syndrome. In some embodiments, the heart disease isinfiltrative cardiomyopathy. In some embodiments, the heart disease is acondition that is or is related to cardiac senescence or diastolicdysfunction due to aging. In some embodiments, the heart disease is acondition that is or is related to left ventricular hypertrophy and/orconcentric left ventricular remodeling.

In some embodiments, the provided are methods of treating a disease orcondition associated with secondary left ventricular wall thickening ina subject, comprising administering to the subject in need thereof aformulation or a tablet as described herein. In some embodiments, thedisease is hypertension, valvular heart diseases (aortic stenosis,Mitral valve regurgitation), metabolic syndromes (diabetes, obesity),end stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry'sdisease, Friedreich Ataxia, Danon disease, Noonan syndrome, or Pompedisease.

Also provided herein is the use of a formulation or a tablet asdescribed herein in the manufacture of a medicament for treatment of adisease or condition associated with secondary left ventricular wallthickening.

In some embodiments, provided are methods of ameliorating a symptomassociated with heart disease in a subject, comprising administering tothe subject in need thereof a formulation or a tablet as describedherein, wherein the symptom is one or more selected from poor or reducedcardiac elasticity, poor or reduced diastolic left ventricularrelaxation, abnormal left atrial pressure (e.g., abnormally high leftatrial pressure), paroxysmal or permanent atrial fibrillation, increasedleft atrial and pulmonary capillary wedge pressures, increased leftventricular diastolic pressures, syncope, ventricular relaxation duringdiastole, ventricular fibrosis, left ventricular hypertrophy, leftventricular mass, increased left ventricular wall thickness, leftventricular mid-cavity obstruction, increased systolic anterior motionof mitral valve, left ventricular outflow tract obstruction, chest pain,exertional dyspnea, pre-syncope, abnormal exercise capacity, andfatigue.

In some embodiments, the provided are methods of reducing the risk of asymptom associated with heart disease in a subject, comprisingadministering to the subject in need thereof a formulation or a tabletas described herein, wherein the symptom is one or more selected fromsudden cardiac death, poor or reduced cardiac elasticity, poor orreduced diastolic left ventricular relaxation, abnormal left atrialpressure (e.g., abnormally high left atrial pressure), paroxysmal orpermanent atrial fibrillation, increased left atrial and pulmonarycapillary wedge pressures, increased left ventricular diastolicpressures, syncope, ventricular relaxation during diastole, ventricularfibrosis, left ventricular hypertrophy, left ventricular mass, increasedleft ventricular wall thickness, left ventricular mid-cavityobstruction, increased systolic anterior motion of mitral valve, leftventricular outflow tract obstruction, chest pain, exertional dyspnea,pre-syncope, abnormal exercise capacity, and fatigue.

In some embodiments, the provided are methods of treating a disease orcondition associated with small left ventricular cavity, cavityobliteration, hyperdynamic left ventricular contraction, obstruction ofblood flow out of the left ventricle, cardiac hypertrophy, small cardiacstroke volume, impaired relaxation of the left ventricle, high leftventricle filling pressure, myocardial ischemia, or cardiac fibrosis ina subject, comprising administering to the subject in need thereof aformulation or a tablet as described herein.

In some embodiments, the provided are methods of treating a disease orcondition associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis in a subject, comprising administering tothe subject in need thereof a formulation or a tablet as describedherein.

Also provided herein is the use of a formulation or a tablet asdescribed herein in the manufacture of a medicament for treatment of adisease or condition associated with small left ventricular cavity andcavity obliteration, hyperdynamic left ventricular contraction,myocardial ischemia, or cardiac fibrosis.

In some embodiments, the provided are methods of treating musculardystrophies in a subject (e.g., Duchenne muscular dystrophy), comprisingadministering to the subject in need thereof a formulation or a tabletas described herein. Also provided herein is the use of a formulation ora tablet as described herein in the manufacture of a medicament fortreatment of muscular dystrophies (e.g., Duchenne muscular dystrophy).

In some embodiments, the provided are methods of treating a glycogenstorage disease in a subject, comprising administering to the subject inneed thereof a formulation or a tablet as described herein. Alsoprovided herein is the use of a formulation or a tablet as describedherein in the manufacture of a medicament for treatment of a glycogenstorage disease.

Also provided are methods for modulating the cardiac sarcomere in asubject which method comprises administering to a subject in needthereof a therapeutically effective amount of a formulation or a tabletas described herein. In some embodiments, provided are methods ofinhibiting the cardiac sarcomere, comprising contacting the cardiacsarcomere with a formulation or a tablet as described herein.Additionally provided herein is the use of a formulation or a tablet asdescribed herein in the manufacture of a medicament for inhibiting thecardiac sarcomere of a subject.

Also provided are methods for potentiating cardiac myosin in a subjectwhich method comprises administering to a subject in need thereof atherapeutically effective amount of a formulation or a tablet asdescribed herein. Additionally provided herein is the use of aformulation or a tablet as described herein in the manufacture of amedicament for potentiating cardiac myosin in a subject.

In some embodiments, the methods provided herein further comprisemonitoring the effectiveness of the treatment. Examples of indicatorsinclude, but are not limited to improvement in one or more of thefollowing: New York Heart Association (NYHA) Functional Classification,exercise capacity, cardiac elasticity, diastolic left ventricularrelaxation, left atrial pressure, paroxysmal or permanent atrialfibrillation, left atrial and pulmonary capillary wedge pressures, leftventricular diastolic pressures, syncope, ventricular relaxation duringdiastole, ventricular fibrosis, left ventricular hypertrophy, leftventricular mass, left ventricular wall thickness, left ventricularmid-cavity obstruction systolic anterior motion of mitral valve, leftventricular outflow tract obstruction, chest pain, exertional dyspnea,pre-syncope, abnormal exercise capacity, and fatigue. These indicatorscan be monitored by techniques known in the art includingself-reporting; ECG, including ambulatory ECG; echocardiography; cardiacMRI; CT; biopsy; cardiopulmonary exercise testing (CPET); andactigraphy.

In some embodiments, the formulation or tablet described and/ordisclosed herein reduces the contractility of a cardiomyocyte. In someembodiments, the formulation or tablet described and/or disclosed hereinreduces the contractility of a cardiomyocyte by greater than 40%, suchas greater than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments,the formulation or tablet described and/or disclosed herein reduced thecontractility of a cardiomyocyte 40%-90%, such as 40%-80%, 40-70%,50%-90%, 50%-80% or 50%-70%. In some embodiments, the formulation ortablet described and/or disclosed herein does not significantly altercalcium transients in the cardiomyocyte. In some embodiments, theformulation or tablet described and/or disclosed herein decreases theATPase activity in a cardiomyocyte. Methods of measuring contractility,ATPase activity, and calcium transients are known in the art, forexample, by calcium labeling, electrophysiological recordings, andmicroscopic imaging. In some embodiments, the formulation or tabletdescribed and/or disclosed herein does not significantly inhibit orinduce a cytochrome P450 (CYP) protein.

In some embodiments, the subject has a left ventricular wall that isthicker than normal prior to treatment. In some embodiments, the subjecthas a left ventricular wall thickness that is greater than 15 mm, suchas greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm prior to treatment.In some embodiments, the left ventricular wall thickness is reduced bygreater than 5%, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%following treatment. Left ventricular wall thickness can be measured bymethods known in the art, such as by echocardiography, CT scan, or acardiac MRI.

In some embodiments, the subject has abnormal cardiac fibrosis prior totreatment. In some embodiments, the abnormal cardiac fibrosis is reducedby greater than 5%, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%following treatment. Cardiac fibrosis can be measured by methods knownin the art, such as by biopsy or a cardiac MRI.

In some embodiments, the subject has reduced exercise capacity prior totreatment. In some embodiments, the exercise capacity of the subject isincreased by greater than 5%, such as greater than 8%, 10%, 12%, 15%,20% or 30% following treatment. In some embodiments, the exercisecapacity is measured by cardiopulmonary exercise testing (CPET). CPETmeasures changes in oxygen consumption (VO₂ max). Methods of measuringCPET and V02 max are well known in the art (Malhotra et al., JACC: HeartFailure, 2016, 4(8): 607-616; Guazzi et al., J Amer College Cardiol,2017, 70 (13): 1618-1636; Rowin et al., JACC: Cariovasc Imaging, 2017,10(11):1374-1386). In some embodiments, V02 max is improved by more than1 mL/kg/m², such as more than 1.2 mL/kg/m², 1.4 mL/kg/m², 1.5 mL/kg/m²,1.7 mL/kg/m², 2 mL/kg/m², 2.2 mL/kg/m², 2.5 mL/kg/m², 3 mL/kg/m², 3.2mL/kg/m², or 3.5 mL/kg/m² following treatment.

In some embodiments, the subject has a New York Heart Association (NYHA)Functional Classification of II, III, or IV prior to treatment. In someembodiments, the subject has a New York Heart Association (NYHA)Functional Classification of III or IV prior to treatment. In someembodiments, the subject has a New York Heart Association (NYHA)Functional Classification of IV prior to treatment. In some embodiments,the subject remains in the same NYHA functional class or has a reducedNYHA functional class following treatment.

In some embodiments, VO₂ max is improved by more than 1 mL/kg/m², suchas more than 1.2 mL/kg/m², 1.4 mL/kg/m², 1.5 mL/kg/m², 1.7 mL/kg/m², or2 mL/kg/m² and the subject has a reduced NYHA functional class followingtreatment. In some embodiments, VO₂ max is improved by more than 2.5mL/kg/m², 3 mL/kg/m², 3.2 mL/kg/m², or 3.5 mL/kg/m² and the subjectremains in the same NYHA functional class or has a reduced NYHAfunctional class following treatment.

In some embodiments, daily function and/or activity level of the subjectis improved following treatment. Improved daily function and/or activitylevel may be measured, for example, by journaling or actigraphy, such asa FITBIT® or FITBIT®-like monitors.

In some embodiments, the subject has one or more of decreased shortnessof breath, decreased chest pain, decreased arrhythmia burden, such asatrial fibrillation and ventricular arrhythmias, decreased incidence ofheart failure, and decreased ventricular outflow obstruction followingtreatment.

Kits

Also provided are articles of manufacture and kits containing any of theformulation or tablet provided herein. The article of manufacture maycomprise a container with a label. Suitable containers include, forexample, bottles, vials, and test tubes. The containers may be formedfrom a variety of materials such as glass or plastic. The container mayhold a pharmaceutical composition provided herein. The label on thecontainer may indicate that the pharmaceutical composition is used forpreventing, treating or suppressing a condition described herein, andmay also indicate directions for either in vivo or in vitro use.

In one aspect, provided herein are kits containing a formulation or atablet as described herein and instructions for use. The kits maycontain instructions for use in the treatment of a heart disease in asubject in need thereof. A kit may also contain sterile packaging.

Combinations

The formulation or tablet described and/or disclosed herein may beadministered alone or in combination with other therapies and/ortherapeutic agents useful in the treatment of the aforementioneddisorders, diseases, or conditions.

The formulation or tablet described and/or disclosed herein may becombined with one or more other therapies to treat a heart disease, suchas HCM or HFpEF. In some embodiments, the one or more therapies includetherapies that retard the progression of heart failure bydown-regulating neurohormonal stimulation of the heart and attempt toprevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptorblockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuralendopeptidase inhibitors). In some embodiments, the one or moretherapies include therapies that improve cardiac function by stimulatingcardiac contractility (e.g., positive inotropic agents, such as theβ-adrenergic agonist dobutamine or the phosphodiesterase inhibitormilrinone). In other embodiments, the one or more therapies includetherapies that reduce cardiac preload (e.g., diuretics, such asfurosemide) or afterload (vasodilators of any class, including but notlimited to calcium channel blockers, phosphodiesterase inhibitors,endothelin receptor antagonists, renin inhibitors, or smooth musclemyosin modulators).

The formulation or tablet described and/or disclosed herein may becombined with one or more other therapies to treat HCM or HFpEF. In someembodiments, the formulation or tablet described and/or disclosed hereinmay be combined with a β-blocker, verapamil, and/or disopyramide.

Enumerated Embodiments

Embodiment 1. A formulation comprising:

-   -   (i)        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or a hydrate, solvate, polymorph, or pharmaceutically acceptable        salt thereof;    -   (ii) a filler;    -   (iii) a binder;    -   (iv) a disintegrant;    -   (v) a surfactant; and    -   (vi) a lubricant.

Embodiment 2. The formulation of embodiment 1, wherein the filler isselected from the group consisting of powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose,kaolin, corn starch, maize starch, starch derivatives, pregelatinizedstarch, calcium phosphate, calcium hydrogen phosphate, dicalciumphosphate, tricalcium phosphate, compressible sugar, sugar alcohol,mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose,maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates,trehalose, maltodextrines, and mixtures of any of the foregoing.

Embodiment 3. The formulation of embodiment 1 or 2, wherein the binderis selected from the group consisting of arabic gum, acacia gum,alginate, alginic acid, corn starch, copolyvidone, polyvinylpyrrolidone,gelatin, glyceryl behenate, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, methylcellulose, hypromellose, lactose,polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates, potatostarch, pregelatinized starch, sodium alginate, sodium starch, sodiumcarboxy methyl cellulose, starch, and mixtures of any of the foregoing.

Embodiment 4. The formulation of any one of embodiments 1-3, wherein thedisintegrant is selected from the group consisting of alginic acid,croscarmellose sodium, cellulose, carboxymethylcellulose calcium,carboxymethylcellulose, sodium, microcrystalline cellulose,crospovidone, sodium starch glycolate, low-substituted hydroxypropylcellulose, polacrillin potassium, pregelatinized starch, partiallyhydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate,sodium carboxy methyl cellulose, and mixtures of any of the foregoing.

Embodiment 5. The formulation of any one of embodiments 1-4, wherein thesurfactant is selected from the group consisting of cetylpyridinechloride, heptadecaethylene oxycetanol, lecithins, polyoxyethylenestearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acidesters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbates,polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60,polysorbate 61, polysorbate 65, polysorbate 80, sodium salts of fattyalcohol sulfates, sodium lauryl sulfate, sodium salts ofsulfosuccinates, sodium dioctylsulfosuccinate, partial esters of fattyacids with alcohols, glycerine monostearate, glyceryl monooleate, ethersof fatty alcohols with polyoxyethylene, esters of fatty acids withpolyoxyethylene, copolymers of ethylenoxide and propylenoxide(Pluronic®,), benzalkonium chloride, ethoxylated triglycerides, andmixtures of any of the foregoing.

Embodiment 6. The formulation of any one of embodiments 1-5, wherein thelubricant is selected from the group consisting of hydrogenated castoroil, magnesium stearate, glyceryl monostearate, calcium stearate,glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate,behenoyl polyoxyl-8 glycerides, sodium stearyl fumarate, stearic acid,talc, zinc stearate, mineral oil, polyethylene glycol, polaxamer, sodiumlauryl sulfate, and mixtures of any of the foregoing.

Embodiment 7. The formulation of any one of embodiments 1-6, wherein theformulation comprises:

-   -   (i) about 1% by weight to about 80% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii) about 15% by weight to about 90% by weight of the filler;    -   (iii) about 0.1% by weight to about 10% by weight of the binder;    -   (iv) about 1% by weight to about 10% by weight of the        disintegrant;    -   (v) about 0.1% by weight to about 10% by weight of the        surfactant; and    -   (vi) about 0.1% by weight to about 10% by weight of the        lubricant.

Embodiment 8. The formulation of any one of embodiments 1-7, wherein theformulation comprises:

-   -   (i) about 1% by weight to about 50% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii) about 40% by weight to about 80% by weight of the filler;    -   (iii) about 0.5% by weight to about 5% by weight of the binder;    -   (iv) about 2% by weight to about 8% by weight of the        disintegrant;    -   (v) about 0.5% by weight to about 5% by weight of the        surfactant; and    -   (vi) about 0.5% by weight to about 5% by weight of the        lubricant.

Embodiment 9. The formulation of any one of embodiments 1-8, wherein theformulation comprises:

-   -   (i) about 10% by weight to about 30% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-p        yrazole-4-carboxamide, or the hydrate, solvate, polymorph, or        pharmaceutically acceptable salt thereof;    -   (ii) about 60% by weight to about 80% by weight of the filler;    -   (iii) about 1% by weight to about 3% by weight of the binder;    -   (iv) about 4% by weight to about 6% by weight of the        disintegrant;    -   (v) about 1% by weight to about 3% by weight of the surfactant;        and    -   (vi) about 0.5% by weight to about 1.5% by weight of the        lubricant.

Embodiment 10. The formulation of any one of embodiments 1-9, whereinthe formulation comprises:

-   -   (i) about 20% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii) about 70% by weight of the filler;    -   (iii) about 2% by weight of the binder;    -   (iv) about 5% by weight of the disintegrant;    -   (v) about 2% by weight of the surfactant; and    -   (vi) about 1% by weight of the lubricant.

Embodiment 11. The formulation of any one of embodiments 1-8, whereinthe formulation comprises:

-   -   (i) about 1% by weight to about 10% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-p        yrazole-4-carboxamide, or the hydrate, solvate, polymorph, or        pharmaceutically acceptable salt thereof;    -   (ii) about 70% by weight to about 90% by weight of the filler;    -   (iii) about 1% by weight to about 3% by weight of the binder;    -   (iv) about 4% by weight to about 6% by weight of the        disintegrant;    -   (v) about 1% by weight to about 3% by weight of the surfactant;        and    -   (vi) about 0.5% by weight to about 1.5% by weight of the        lubricant.

Embodiment 12. The formulation of any one of embodiments 1-8 and 11,wherein the formulation comprises:

-   -   (i) about 5% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii) about 85% by weight of the filler;    -   (iii) about 2% by weight of the binder;    -   (iv) about 5% by weight of the disintegrant;    -   (v) about 2% by weight of the surfactant; and    -   (vi) about 1% by weight of the lubricant.

Embodiment 13. The formulation of any one of embodiments 1-9 and 11,wherein the formulation comprises:

-   -   (i) about 10% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii) about 80% by weight of the filler;    -   (iii) about 2% by weight of the binder;    -   (iv) about 5% by weight of the disintegrant;    -   (v) about 2% by weight of the surfactant; and    -   (vi) about 1% by weight of the lubricant.

Embodiment 14. The formulation of any one of embodiments 1-13, whereinthe filler comprises mannitol.

Embodiment 15. The formulation of any one of embodiments 1-14, whereinthe filler comprises microcrystalline cellulose.

Embodiment 16. The formulation of any one of embodiments 1-15, whereinthe filler consists of mannitol and microcrystalline cellulose.

Embodiment 17. The formulation of any one of embodiments 1-16, whereinthe binder is hydroxypropyl cellulose.

Embodiment 18. The formulation of any one of embodiments 1-17, whereinthe disintegrant is croscarmellose sodium.

Embodiment 19. The formulation of any one of embodiments 1-18, whereinthe surfactant is sodium lauryl sulfate.

Embodiment 20. The formulation of any one of embodiments 1-19, whereinthe lubricant is magnesium stearate.

Embodiment 21. The formulation of any one of embodiments 1-8, whereinthe formulation comprises:

-   -   (i) about 1% by weight to about 50% by weight of        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 10% by weight to about 60% by weight of mannitol;    -   (ii-2) about 5% by weight to about 45% by weight of        microcrystalline cellulose;    -   (iii) about 0.1% by weight to about 10% by weight of        hydroxypropyl cellulose;    -   (iv) about 1% by weight to about 10% by weight of croscarmellose        sodium;    -   (v) about 0.1% by weight to about 10% by weight of sodium lauryl        sulfate; and    -   (vi) about 0.1% by weight to about 10% by weight of magnesium        stearate.

Embodiment 22. The formulation of any one of embodiments 1-8 and 21,wherein the formulation comprises:

-   -   (i) about 10% by weight to about 30% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 40% by weight to about 50% by weight of mannitol;    -   (ii-2) about 20% by weight to about 30% by weight of        microcrystalline cellulose;    -   (iii) about 1% by weight to about 3% by weight of hydroxypropyl        cellulose;    -   (iv) about 4% by weight to about 6% by weight of croscarmellose        sodium;    -   (v) about 1% by weight to about 3% by weight of sodium lauryl        sulfate; and    -   (vi) about 0.5% by weight to about 1.5% by weight of magnesium        stearate.

Embodiment 23. The formulation of any one of embodiments 1-8 and 21,wherein the formulation comprises:

-   -   (i) about 1% by weight to about 10% by weight of        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 50% by weight to about 60% by weight of mannitol;    -   (ii-2) about 25% by weight to about 35% by weight of        microcrystalline cellulose;    -   (iii) about 1% by weight to about 3% by weight of hydroxypropyl        cellulose;    -   (iv) about 4% by weight to about 6% by weight of croscarmellose        sodium;    -   (v) about 1% by weight to about 3% by weight of sodium lauryl        sulfate; and    -   (vi) about 0.5% by weight to about 1.5% by weight of the        magnesium stearate.

Embodiment 24. The formulation of any one of embodiments 1-8, 21, and22, wherein the formulation comprises:

-   -   (i) about 20% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 44% by weight of mannitol;    -   (ii-2) about 26% by weight of microcrystalline cellulose;    -   (iii) about 2% by weight of hydroxypropyl cellulose;    -   (iv) about 5% by weight of croscarmellose sodium;    -   (v) about 2% by weight of sodium lauryl sulfate; and    -   (vi) about 1% by weight of magnesium stearate.

Embodiment 25. The formulation of any one of embodiments 1-8, 21-23,wherein the formulation comprises:

-   -   (i) about 10% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 50% by weight of mannitol;    -   (ii-2) about 30% by weight of microcrystalline cellulose;    -   (iii) about 2% by weight of hydroxypropyl cellulose;    -   (iv) about 5% by weight of croscarmellose sodium;    -   (v) about 2% by weight of sodium lauryl sulfate; and    -   (vi) about 1% by weight of the magnesium stearate.

Embodiment 26. The formulation of any one of embodiments 1-8, 21 and 23,wherein the formulation comprises:

-   -   (i) about 5% by weight of the        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof;    -   (ii-1) about 54% by weight of mannitol;    -   (ii-2) about 31% by weight of microcrystalline cellulose;    -   (iii) about 2% by weight of hydroxypropyl cellulose;    -   (iv) about 5% by weight of croscarmellose sodium;    -   (v) about 2% by weight of sodium lauryl sulfate; and    -   (vi) about 1% by weight of the magnesium stearate.

Embodiment 27. The formulation of any of the preceding embodiments,wherein the formulation is for oral administration.

Embodiment 28. The formulation of any of the preceding embodiments,wherein the formulation is for administration once daily.

Embodiment 29. The formulation of any of the preceding embodiments,wherein the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, is(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

Embodiment 30. A tablet comprising:

-   (i) a core having a total core weight comprising:    -   (a) an intra-granular component comprising:        -   (a-i)            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or a hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) an intra-granular filler;        -   (a-iii) an intra-granular binder;        -   (a-iv) an intra-granular disintegrant; and        -   (a-v) an intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) an extra-granular filler;        -   (b-ii) an extra-granular disintegrant; and        -   (b-iii) an extra-granular lubricant;-   and optionally-   (ii) a coating layer comprising a coating agent.

Embodiment 31. The tablet of embodiment 30, wherein the intra-granularfiller is selected from the group consisting of powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose,kaolin, corn starch, maize starch, starch derivatives, pregelatinizedstarch, calcium phosphate, calcium hydrogen phosphate, dicalciumphosphate, tricalcium phosphate, compressible sugar, sugar alcohol,mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose,maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates,trehalose, maltodextrines, and mixtures of any of the foregoing.

Embodiment 32. The tablet of embodiment 30 or 31, wherein theintra-granular binder is selected from the group consisting of arabicgum, acacia gum, alginate, alginic acid, corn starch, copolyvidone,polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethylcellulose,hydroxypropyl cellulose, carboxymethylcellulose. carboxymethylcellulosecalcium, carboxymethylcellulose sodium, methylcellulose, hypromellose,lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates,potato starch, pregelatinized starch, sodium alginate, sodium starch,sodium carboxy methyl cellulose, starch, and mixtures of any of theforegoing.

Embodiment 33. The tablet of any one of embodiments 30-32, wherein theintra-granular disintegrant is selected from the group consisting ofalginic acid, croscarmellose sodium, cellulose, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, microcrystalline cellulose,crospovidone, sodium starch glycolate, low-substituted hydroxypropylcellulose, polacrillin potassium, pregelatinized starch, partiallyhydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate,sodium carboxy methyl cellulose, and mixtures of any of the foregoing.

Embodiment 34. The tablet of any one of embodiments 30-33, wherein theintra-granular surfactant is selected from the group consisting ofcetylpyridine chloride, heptadecaethylene oxycetanol, lecithins,polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9,sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85,polysorbates, polysorbate 20, polysorbate 21, polysorbate 40,polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodiumsalts of fatty alcohol sulfates, sodium lauryl sulfate, sodium salts ofsulfosuccinates, sodium dioctylsulfosuccinate, partial esters of fattyacids with alcohols, glycerine monostearate, glyceryl monooleate, ethersof fatty alcohols with polyoxyethylene, esters of fatty acids withpolyoxyethylene, copolymers of ethylenoxide and propylenoxide(Pluronic®), benzalkonium chloride, ethoxylated triglycerides, andmixtures of any of the foregoing.

Embodiment 35. The tablet of any one of embodiments 30-34, wherein theextra-granular filler is selected from the group consisting of powderedcellulose, microcrystalline cellulose, silicified microcrystallinecellulose, kaolin, corn starch, maize starch, starch derivatives,pregelatinized starch, calcium phosphate, calcium hydrogen phosphate,dicalcium phosphate, tricalcium phosphate, compressible sugar, sugaralcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose,dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose,dextrates, trehalose, maitodextrines, and mixtures of any of theforegoing.

Embodiment 36. The tablet of any one of embodiments 30-35, wherein theextra-granular disintegrant is selected from the group consisting ofalginic acid, croscarmellose sodium, cellulose, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, microcrystalline cellulose,crospovidone, sodium starch glycolate, low-substituted hydroxypropylcellulose, polacrillin potassium, pregelatinized starch, partiallyhydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate,sodium carboxy methyl cellulose, and mixtures of any of the foregoing.

Embodiment 37. The tablet of any one of embodiments 30-36, wherein theextra-granular lubricant is selected from the group consisting ofhydrogenated castor oil, magnesium stearate, glyceryl monostearate,calcium stearate, glyceryl behenate, glycerol distearate, glyceryldipalmitostearate, behenoyl polyoxyl-8 glycerides, sodium stearylfumarate, stearic acid, talc, zinc stearate, mineral oil, polyethyleneglycol, polaxamer, sodium lauryl sulfate, and mixtures of any of theforegoing.

Embodiment 38. The tablet of any one of embodiments 30-37, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% to about 80% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 10% to about 80% of the total core weight of            the intra-granular filler;        -   (a-iii) about 0.1% to about 10% of the total core weight of            the intra-granular binder;        -   (a-iv) about 0.1% to about 5% of the total core weight of            the intra-granular disintegrant; and        -   (a-v) about 0.1% to about 5% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of the            extra-granular filler;        -   (b-ii) about 0.1% to about 5% of the total core weight of            the extra-granular disintegrant; and        -   (b-iii) about 0.1% to about 5% of the total core weight of            the extra-granular lubricant.

Embodiment 39. The tablet of any one of embodiments 30-38, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% to about 50% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 40% to about 80% of the total core weight of            the intra-granular filler;        -   (a-iii) about 1% to about 5% of the total core weight of the            intra-granular binder;        -   (a-iv) about 1% to about 5% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 1% to about 5% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:    -   (b-i) about 5% to about 15% of the total core weight of the        extra-granular filler;    -   (b-ii) about 1% to about 5% of the total core weight of the        extra-granular disintegrant; and    -   (b-iii) about 0.1% to about 2% of the total core weight of the        extra-granular lubricant.

Embodiment 40. The tablet of any one of embodiments 30-39, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% to about 30% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 50% to about 70% of the total core weight of            the intra-granular filler;        -   (a-iii) about 1% to about 3% of the total core weight of the            intra-granular binder;        -   (a-iv) about 2% to about 4% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 1% to about 3% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of the            an extra-granular filler;        -   (b-ii) about 1% to about 3% of the total core weight of the            extra-granular disintegrant; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            the extra-granular lubricant.

Embodiment 41. The tablet of any one of embodiments 30-39, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% to about 10% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 60% to about 80% of the total core weight of            the intra-granular filler;        -   (a-iii) about 1% to about 3% of the total core weight of the            intra-granular binder;        -   (a-iv) about 2% to about 4% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 1% to about 3% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of the            an extra-granular filler;        -   (b-ii) about 1% to about 3% of the total core weight of the            extra-granular disintegrant; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            the extra-granular lubricant.

Embodiment 42. The tablet of any one of embodiments 30-39 and 41,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 5% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 74% of the total core weight of the            intra-granular filler;        -   (a-iii) about 2% of the total core weight of the            intra-granular binder;        -   (a-iv) about 3% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 2% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of the an            extra-granular filler;        -   (b-ii) about 2% of the total core weight of the            extra-granular disintegrant; and        -   (b-iii) about 1% of the total core weight of the            extra-granular lubricant.

Embodiment 43. The tablet of any one of embodiments 30-41, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 69% of the total core weight of the            intra-granular filler;        -   (a-iii) about 2% of the total core weight of the            intra-granular binder;        -   (a-iv) about 3% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 2% of the total core weight of the            intra-granular surfactant; and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of the an            extra-granular filler;        -   (b-ii) about 2% of the total core weight of the            extra-granular disintegrant; and        -   (b-iii) about 1% of the total core weight of the            extra-granular lubricant.

Embodiment 44. The tablet of any one of embodiments 30-40, wherein thecore comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 20% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii) about 59% of the total core weight of the            intra-granular filler;        -   (a-iii) about 2% of the total core weight of the            intra-granular binder;        -   (a-iv) about 3% of the total core weight of the            intra-granular disintegrant; and        -   (a-v) about 2% of the total core weight of the            intra-granular surfactant;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of the an            extra-granular filler;        -   (b-ii) about 2% of the total core weight of the            extra-granular disintegrant; and        -   (b-iii) about 1% of the total core weight of the            extra-granular lubricant.

Embodiment 45. The tablet of any one of embodiments 30-44, wherein theintra-granular filler comprises mannitol.

Embodiment 46. The tablet of any one of embodiments 30-45, wherein theintra-granular filler comprises microcrystalline cellulose.

Embodiment 47. The tablet of any one of embodiments 30-46, wherein theintra-granular filler consists of mannitol and microcrystallinecellulose.

Embodiment 48. The tablet of any one of embodiments 30-47, wherein theintra-granular binder is hydroxypropyl cellulose.

Embodiment 49. The tablet of any one of embodiments 30-48, wherein theintra-granular disintegrant is croscarmellose sodium.

Embodiment 50. The tablet of any one of embodiments 30-49, wherein theintra-granular surfactant is sodium lauryl sulfate.

Embodiment 51. The tablet of any one of embodiments 30-50, wherein theextra-granular filler is microcrystalline cellulose.

Embodiment 52. The tablet of any one of embodiments 30-51, wherein theextra-granular disintegrant is croscarmellose sodium.

Embodiment 53. The tablet of any one of embodiments 30-52, wherein theextra-granular lubricant is magnesium stearate.

Embodiment 54. The tablet of any one of embodiments 30-39 and 45-52,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% to about 50% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 40% to about 60% of the total core weight of            mannitol;        -   (a-ii-2) about 10% to about 30% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 5% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 1% to about 5% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 5% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 5% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 2% of the total core weight of            extra-granular lubricant.

Embodiment 55. The tablet of any one of embodiments 30-39 and 45-53,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% to about 50% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 40% to about 60% of the total core weight of            mannitol;        -   (a-ii-2) about 10% to about 30% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 5% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 1% to about 5% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 5% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 5% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 2% of the total core weight of            magnesium stearate.

Embodiment 56. The tablet of any one of embodiments 30-40, 45-52, and54, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% to about 30% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 40% to about 50% of the total core weight of            mannitol;        -   (a-ii-2) about 10% to about 20% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 3% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 2% to about 4% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 3% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 3% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            extra-granular lubricant.

Embodiment 57. The tablet of any one of embodiments 30-40, 45-56,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% to about 30% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 40% to about 50% of the total core weight of            mannitol;        -   (a-ii-2) about 10% to about 20% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 3% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 2% to about 4% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 3% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 3% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            magnesium stearate.

Embodiment 58. The tablet of any one of embodiments 30-39, 41, 45-52,and 54, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% by weight to about 10% of the total core            weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 50% to about 60% of the total core weight of            mannitol;        -   (a-ii-2) about 15% to about 25% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 3% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 2% to about 4% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 3% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 3% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            extra-granular lubricant.

Embodiment 59. The tablet of any one of embodiments 30-39, 41, 45-55,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 1% by weight to about 10% of the total core            weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 50% to about 60% of the total core weight of            mannitol;        -   (a-ii-2) about 15% to about 25% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 1% to about 3% of the total core weight of            hydroxypropyl cellulose;        -   (a-iv) about 2% to about 4% of the total core weight of            croscarmellose sodium; and        -   (a-v) about 1% to about 3% of the total core weight of            sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5% to about 15% of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 1% to about 3% of the total core weight of            croscarmellose sodium; and        -   (b-iii) about 0.1% to about 1.5% of the total core weight of            magnesium stearate.

Embodiment 60. The tablet of any one of embodiments 30-39, 41, 42,45-52, 54, and 58, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 5% by weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 54% by weight of mannitol;        -   (a-ii-2) about 20% by weight of microcrystalline cellulose;        -   (a-iii) about 2% by weight of hydroxypropyl cellulose;        -   (a-iv) about 3% by weight of croscarmellose sodium; and        -   (a-v) about 2% by weight of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% by weight of microcrystalline cellulose;        -   (b-ii) about 2% by weight of croscarmellose sodium; and        -   (b-iii) about 1% by weight of extra-granular lubricant.

Embodiment 61. The tablet of any one of embodiments 30-39, 41, 42,45-55, 58, and 59, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 5% by weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 54% by weight of mannitol;        -   (a-ii-2) about 20% by weight of microcrystalline cellulose;        -   (a-iii) about 2% by weight of hydroxypropyl cellulose;        -   (a-iv) about 3% by weight of croscarmellose sodium; and        -   (a-v) about 2% by weight of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% by weight of microcrystalline cellulose;        -   (b-ii) about 2% by weight of croscarmellose sodium; and        -   (b-iii) about 1% by weight of magnesium stearate.

Embodiment 62. The tablet of any one of embodiments 30-41, 45-52, 54,56, and 58, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 50% of the total core weight of mannitol;        -   (a-ii-2) about 19% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2% of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3% of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2% of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of microcrystalline            cellulose;        -   (b-ii) about 2% of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 1% of the total core weight of extra-granular            lubricant.

Embodiment 63. The tablet of any one of embodiments 30-41 and 45-59,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 50% of the total core weight of mannitol;        -   (a-ii-2) about 19% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2% of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3% of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2% of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:    -   (b-i) about 11% of the total core weight of microcrystalline        cellulose;    -   (b-ii) about 2% of the total core weight of croscarmellose        sodium; and    -   (b-iii) about 1% of the total core weight of magnesium stearate.

Embodiment 64. The tablet of any one of embodiments 30-40, 44-52, 54,and 56, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 20% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 44% of the total core weight of mannitol;        -   (a-ii-2) about 15% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2% of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3% of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2% of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of microcrystalline            cellulose;        -   (b-ii) about 2% of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 1% of the total core weight of extra-granular            lubricant.

Embodiment 65. The tablet of any one of embodiments 30-40, 44-57,wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 20% of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 44% of the total core weight of mannitol;        -   (a-ii-2) about 15% of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2% of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3% of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2% of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11% of the total core weight of microcrystalline            cellulose;        -   (b-ii) about 2% of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 1% of the total core weight of magnesium            stearate.

Embodiment 66. The tablet of any one of embodiments 30-65, comprising acoating layer.

Embodiment 67. The tablet of any one of embodiments 30-66, wherein thecoating agent is selected from the group consisting of Opadry QX White21A180025, Opadry I, and Opadry II.

Embodiment 68. The tablet of any one of embodiments 30-67, wherein thecoating agent is Opadry QX White 21A180025.

Embodiment 69. The tablet of any one of embodiments 30-68, wherein thetablet comprises about 0.5% to about 10% of the total core weight ofcoating agent.

Embodiment 70. The tablet of any one of embodiments 30-69, wherein thetablet comprises about 1% to about 5% of the total core weight ofcoating agent.

Embodiment 71. The tablet of any one of embodiments 30-71, wherein thetablet comprises about 2% to about 4% of the total core weight ofcoating agent.

Embodiment 72. The tablet of any one of embodiments 30-71, wherein thetablet comprises about 3% of the total core weight of coating agent.

Embodiment 73. The tablet of any one of embodiments 30-72, wherein thetotal core weight is about 50 mg.

Embodiment 74. The tablet of embodiment 73, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 2.5 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 27 mg of mannitol;        -   (a-ii-2) about 10 mg of microcrystalline cellulose;        -   (a-iii) about 1 mg of hydroxypropyl cellulose;        -   (a-iv) about 1.5 mg of croscarmellose sodium; and        -   (a-v) about 1 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5.5 mg of microcrystalline cellulose;        -   (b-ii) about 1 mg of croscarmellose sodium; and        -   (b-iii) about 0.5 mg of extra-granular lubricant.

Embodiment 75. The tablet of embodiment 73 or 74, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 2.5 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 27 mg of mannitol;        -   (a-ii-2) about 10 mg of microcrystalline cellulose;        -   (a-iii) about 1 mg of hydroxypropyl cellulose;        -   (a-iv) about 1.5 mg of croscarmellose sodium; and        -   (a-v) about 1 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 5.5 mg of microcrystalline cellulose;        -   (b-ii) about 1 mg of croscarmellose sodium; and        -   (b-iii) about 0.5 mg of magnesium stearate.

Embodiment 76. The tablet of any one of embodiments 73-75, wherein thetablet comprises about 1.5 mg of coating agent.

Embodiment 77. The tablet of embodiment 76, wherein the coating agent isOpadry QX White 21A180025

Embodiment 78. The tablet of any one of embodiments 30-72, wherein thetotal core weight is about 100 mg.

Embodiment 79. The tablet of embodiment 78, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 5 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 54 mg of mannitol;        -   (a-ii-2) about 20 mg of microcrystalline cellulose;        -   (a-iii) about 2 mg of hydroxypropyl cellulose;        -   (a-iv) about 3 mg of croscarmellose sodium; and        -   (a-v) about 2 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11 mg of microcrystalline cellulose;        -   (b-ii) about 2 mg of croscarmellose sodium; and        -   (b-iii) about 1 mg of extra-granular lubricant.

Embodiment 80. The tablet of embodiment 78 or 79, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 5 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 54 mg of mannitol;        -   (a-ii-2) about 20 mg of microcrystalline cellulose;        -   (a-iii) about 2 mg of hydroxypropyl cellulose;        -   (a-iv) about 3 mg of croscarmellose sodium; and        -   (a-v) about 2 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11 mg of microcrystalline cellulose;        -   (b-ii) about 2 mg of croscarmellose sodium; and        -   (b-iii) about 1 mg of magnesium stearate.

Embodiment 81. The tablet of embodiment 78, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 20 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 44 mg of the total core weight of mannitol;        -   (a-ii-2) about 15 mg of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2 mg of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3 mg of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2 mg of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11 mg of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 2 mg of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 1 mg of the total core weight of            extra-granular lubricant.

Embodiment 82. The tablet of embodiment 78 or 81, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 20 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 44 mg of the total core weight of mannitol;        -   (a-ii-2) about 15 mg of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 2 mg of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 3 mg of the total core weight of croscarmellose            sodium; and        -   (a-v) about 2 mg of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 11 mg of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 2 mg of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 1 mg of the total core weight of magnesium            stearate.

Embodiment 83. The tablet of any one of embodiments 78-82, wherein thetablet comprises about 3 mg of coating agent.

Embodiment 84. The tablet of embodiment 83, wherein the coating agent isOpadry QX White 21A180025

Embodiment 85. The tablet of any one of embodiments 30-72, wherein thetotal core weight is about 200 mg.

Embodiment 86. The tablet of embodiment 85, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 108 mg of mannitol;        -   (a-ii-2) about 40 mg of microcrystalline cellulose;        -   (a-iii) about 4 mg of hydroxypropyl cellulose;        -   (a-iv) about 6 mg of croscarmellose sodium; and        -   (a-v) about 4 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 22 mg of microcrystalline cellulose;        -   (b-ii) about 4 mg of croscarmellose sodium; and        -   (b-iii) about 2 mg of extra-granular lubricant.

Embodiment 87. The tablet of embodiment 85 or 86, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 10 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 108 mg of mannitol;        -   (a-ii-2) about 40 mg of microcrystalline cellulose;        -   (a-iii) about 4 mg of hydroxypropyl cellulose;        -   (a-iv) about 6 mg of croscarmellose sodium; and        -   (a-v) about 4 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 22 mg of microcrystalline cellulose;        -   (b-ii) about 4 mg of croscarmellose sodium; and        -   (b-iii) about 2 mg of magnesium stearate.

Embodiment 88. The tablet of embodiment 85, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 40 mg of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 88 mg of the total core weight of mannitol;        -   (a-ii-2) about 30 mg of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 4 mg of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 6 mg of the total core weight of croscarmellose            sodium; and        -   (a-v) about 4 mg of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 22 mg of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 4 mg of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 2 mg of the total core weight of            extra-granular lubricant.

Embodiment 89. The tablet of embodiment 85 or 88, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 40 mg of the total core weight of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 88 mg of the total core weight of mannitol;        -   (a-ii-2) about 30 mg of the total core weight of            microcrystalline cellulose;        -   (a-iii) about 4 mg of the total core weight of hydroxypropyl            cellulose;        -   (a-iv) about 6 mg of the total core weight of croscarmellose            sodium; and        -   (a-v) about 4 mg of the total core weight of sodium lauryl            sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 22 mg of the total core weight of            microcrystalline cellulose;        -   (b-ii) about 4 mg of the total core weight of croscarmellose            sodium; and        -   (b-iii) about 2 mg of the total core weight of magnesium            stearate.

Embodiment 90. The tablet of any one of embodiments 85-89, wherein thetablet comprises about 6 mg of coating agent.

Embodiment 91. The tablet of embodiment 90, wherein the coating agent isOpadry QX White 21A180025

Embodiment 92. The tablet of any one of embodiments 30-72, wherein thetotal core weight is about 70 mg.

Embodiment 93. The tablet of embodiment 92, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 7 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 35 mg of mannitol;        -   (a-ii-2) about 13.3 mg of microcrystalline cellulose;        -   (a-iii) about 1.4 mg of hydroxypropyl cellulose;        -   (a-iv) about 2.1 mg of croscarmellose sodium; and        -   (a-v) about 1.4 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 7.7 mg of microcrystalline cellulose;        -   (b-ii) about 1.4 mg of croscarmellose sodium; and        -   (b-iii) about 0.7 mg of extra-granular lubricant.

Embodiment 94. The tablet of embodiment 92 or 93, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 7 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 35 mg of mannitol;        -   (a-ii-2) about 13.3 mg of microcrystalline cellulose;        -   (a-iii) about 1.4 mg of hydroxypropyl cellulose;        -   (a-iv) about 2.1 mg of croscarmellose sodium; and        -   (a-v) about 1.4 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 7.7 mg of microcrystalline cellulose;        -   (b-ii) about 1.4 mg of croscarmellose sodium; and        -   (b-iii) about 0.7 mg of magnesium stearate.

Embodiment 95. The tablet of any one of embodiments 92-94, wherein thetablet comprises about 2.1 mg of coating agent.

Embodiment 96. The tablet of embodiment 95, wherein the coating agent isOpadry QX White 21A180025

Embodiment 97. The tablet of any one of embodiments 30-72, wherein thetotal core weight is about 400 mg.

Embodiment 98. The tablet of embodiment 97, wherein the core comprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 40 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 200 mg of mannitol;        -   (a-ii-2) about 76 mg of microcrystalline cellulose;        -   (a-iii) about 8 mg of hydroxypropyl cellulose;        -   (a-iv) about 12 mg of croscarmellose sodium; and        -   (a-v) about 8 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 44 mg of microcrystalline cellulose;        -   (b-ii) about 8 mg of croscarmellose sodium; and        -   (b-iii) about 4 mg of extra-granular lubricant.

Embodiment 99. The tablet of embodiment 97 or 98, wherein the corecomprises:

-   -   (a) an intra-granular component comprising:        -   (a-i) about 40 mg of the            (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,            or the hydrate, solvate, polymorph, or pharmaceutically            acceptable salt thereof;        -   (a-ii-1) about 200 mg of mannitol;        -   (a-ii-2) about 76 mg of microcrystalline cellulose;        -   (a-iii) about 8 mg of hydroxypropyl cellulose;        -   (a-iv) about 12 mg of croscarmellose sodium; and        -   (a-v) about 8 mg of sodium lauryl sulfate;    -   and    -   (b) an extra-granular component comprising:        -   (b-i) about 44 mg of microcrystalline cellulose;        -   (b-ii) about 8 mg of croscarmellose sodium; and        -   (b-iii) about 4 mg of magnesium stearate.

Embodiment 100. The tablet of any one of embodiments 97-98, wherein thetablet comprises about 12 mg of coating agent.

Embodiment 101. The tablet of embodiment 100, wherein the coating agentis Opadry QX White 21A180025

Embodiment 102. The tablet of any one of embodiments 30-101, wherein the(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, or the hydrate, solvate, polymorph, orpharmaceutically acceptable salt thereof, is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

Embodiment 103. A process for making the tablet of any one ofembodiments 30-102, wherein the process comprises:

-   -   (1) preparing granules comprising        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof, the intra-granular filler, the        intra-granular binder, the intra-granular disintegrant, and the        intra-granular surfactant;    -   (2) milling the granules comprising        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof, the intra-granular filler, the        intra-granular binder, the intra-granular disintegrant, and the        intra-granular surfactant to form the intra-granular component;    -   (3) blending the intra-granular component with the        extra-granular filler, the extra-granular disintegrant, and the        extra-granular lubricant to form a final blend mixture;    -   (4) compressing the final blend mixture to form the core;    -   (5) optionally coating the core with the coating layer.

Embodiment 104. The process of embodiment 102, wherein preparinggranules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant comprisesa wet granulation step.

Embodiment 105. The process of embodiment 104, wherein the wetgranulation step is performed with a high shear granulator.

Embodiment 106. The process of embodiment 104 or 105, wherein the wetgranulation step further comprises a wet milling step.

Embodiment 107. The process of embodiment 106, wherein the wet millingstep is performed with a conical mill.

Embodiment 108. The process of any one of embodiments 103-107, whereinpreparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant furthercomprises drying the granules.

Embodiment 109. The process of embodiment 108, wherein drying thegranules is performed in a fluid bed dryer.

Embodiment 110. The process of any one of embodiments 103-109, whereinmilling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant isperformed with a conical mill.

Embodiment 111. The process of any one of embodiments 103-110, whereinblending the intra-granular component with the extra-granular filler,the extra-granular disintegrant, and the extra-granular lubricant isperformed in a V-blender.

Embodiment 112. The process of any one of embodiments 103-111, whereincompressing the final blend mixture to form the core is performed with arotary tablet press.

Embodiment 113. The process of any one of embodiments 103-112,comprising coating the core with the coating layer.

Embodiment 114. The process of any one of embodiments 103-113,comprising coating the core with the coating layer using a conventionalcoating pan.

Embodiment 115. The process of any one of embodiments 103-114, whereinthe(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, is(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

Embodiment 116. A process for making a tablet comprising:

-   -   (i) a core having a total core weight comprising:        -   (a) an intra-granular component comprising:            -   (a-i)                (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,                or a hydrate, solvate, polymorph, or pharmaceutically                acceptable salt thereof;            -   (a-ii) an intra-granular filler;            -   (a-iii) an intra-granular binder;            -   (a-iv) an intra-granular disintegrant; and            -   (a-v) an intra-granular surfactant;        -   and        -   (b) an extra-granular component comprising:            -   (b-i) an extra-granular filler;            -   (b-ii) an extra-granular disintegrant; and            -   (b-iii) an extra-granular lubricant;    -   and    -   (ii) a coating layer comprising a coating agent.

-   wherein the process comprises:    -   (1) preparing granules comprising        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof, the intra-granular filler, the        intra-granular binder, the intra-granular disintegrant, and the        intra-granular surfactant;    -   (2) milling the granules comprising        (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,        or the hydrate, solvate, polymorph, or pharmaceutically        acceptable salt thereof, the intra-granular filler, the        intra-granular binder, the intra-granular disintegrant, and the        intra-granular surfactant to form the intra-granular component;    -   (3) blending the intra-granular component with the        extra-granular filler, the extra-granular disintegrant, and the        extra-granular lubricant to form a final blend mixture;    -   (4) compressing the final blend mixture to form the core;    -   (5) coating the core with the coating layer.

Embodiment 117. The process of embodiment 116, wherein preparinggranules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant comprisesa wet granulation step.

Embodiment 118. The process of embodiment 117, wherein the wetgranulation step is performed with a high shear granulator.

Embodiment 119. The process of embodiment 117 or 118, wherein the wetgranulation step further comprises a wet milling step.

Embodiment 120. The process of embodiment 119, wherein the wet millingstep is performed with a conical mill.

Embodiment 121. The process of any one of embodiments 116-120, whereinpreparing granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant furthercomprises drying the granules.

Embodiment 122. The process of embodiment 121, wherein drying thegranules is performed in a fluid bed dryer.

Embodiment 123. The process of any one of embodiments 116-122, whereinmilling the granules comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, the intra-granular filler, the intra-granular binder, theintra-granular disintegrant, and the intra-granular surfactant isperformed with a conical mill.

Embodiment 124. The process of any one of embodiments 116-123, whereinblending the intra-granular component with the extra-granular filler,the extra-granular disintegrant, and the extra-granular lubricant isperformed in a V-blender.

Embodiment 125. The process of any one of embodiments 116-124, whereincompressing the final blend mixture to form the core is performed with arotary tablet press.

Embodiment 126. The process of any one of embodiments 116-125,comprising coating the core with the coating layer.

Embodiment 127. The process of any one of embodiments 116-126,comprising coating the core with the coating layer using a coating pan.

Embodiment 128. The process of any one of embodiments 116-127, whereinthe(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,or the hydrate, solvate, polymorph, or pharmaceutically acceptable saltthereof, is(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

Embodiment 129. A method of treating heart disease in a subject in needthereof, comprising administering to the subject the formulation of anyone of embodiments 1-29, or the tablet of any one of embodiments 30-102.

Embodiment 130. The method of embodiment 129, wherein the heart diseaseis hypertrophic cardiomyopathy (HCM).

Embodiment 131. The method of embodiment 130, wherein the HCM isobstructive or nonobstructive or is associated with a sarcomeric and/ornon-sarcomeric mutation.

Embodiment 132. The method of embodiment 129, wherein the heart diseaseis heart failure with preserved ejection fraction (HFpEF).

Embodiment 133. The method of embodiment 129, wherein the heart diseaseis selected from the group consisting of diastolic dysfunction, primaryor secondary restrictive cardiomyopathy, myocardial infarction andangina pectoris, left ventricular outflow tract obstruction,hypertensive heart disease, congenital heart disease, cardiac ischemia,coronary heart disease, diabetic heart disease, congestive heartfailure, right heart failure, cardiorenal syndrome, and infiltrativecardiomyopathy.

Embodiment 134. The method of embodiment 129, wherein the heart diseaseis or is related to one or more conditions selected from the groupconsisting of cardiac senescence, diastolic dysfunction due to aging,left ventricular hypertrophy and concentric left ventricular remodeling.

Embodiment 135. A method of treating a disease or condition associatedwith HCM in a subject in need thereof, comprising administering to thesubject the formulation of any one of embodiments 1-29, or the tablet ofany one of embodiments 30-102.

Embodiment 136. The method of embodiment 135, wherein the disease orcondition is selected from the group consisting of Fabry's Disease,Danon Disease, mitochondrial cardiomyopathies, and Noonan Syndrome.

Embodiment 137. A method of treating a disease or condition that isassociated with secondary left ventricular wall thickening in a subjectin need thereof, comprising administering to the subject the formulationof any one of embodiments 1-29, or the tablet of any one of embodiments30-102.

Embodiment 138. The method of embodiment 137, wherein the disease orcondition is selected from the group consisting of hypertension,valvular heart diseases, metabolic syndromes, end stage renal disease,scleroderma, sleep apnea, amyloidosis, Fabry's disease, FriedreichAtaxia, Danon disease, Noonan syndrome, and Pompe disease.

Embodiment 139. A method of treating a disease or condition that isassociated with small left ventricular cavity and cavity obliteration,hyperdynamic left ventricular contraction, myocardial ischemia, orcardiac fibrosis in a subject in need thereof, comprising administeringto the subject the formulation of any one of embodiments 1-29, or thetablet of any one of embodiments 30-102.

Embodiment 140. A method of treating a disease or condition selectedfrom muscular dystrophies and glycogen storage diseases in a subject inneed thereof, comprising administering to the subject the formulation ofany one of embodiments 1-29, or the tablet of any one of embodiments30-102.

Embodiment 141. A method of inhibiting the cardiac sarcomere, comprisingcontacting the cardiac sarcomere with the formulation of any one ofembodiments 1-29, or the tablet of any one of embodiments 30-102.

EXAMPLES

The following examples are offered to illustrate but not to limit thecompositions, uses, and methods provided herein.

The following abbreviations are used throughout the Examples: TEA(trimethylamine), DCM (dichloromethane), (Boc)₂O (di-tert-butyldicarbonate), EA (Ethyl acetate), PE (Petroleum ether, DMF(N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), HOAt (1-Hydroxy-7-azabenzotriazole), HOBt(Hydroxybenzotriazole), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH(ethanol), iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroaceticacid), DPPA (Diphenylphosphoryl azide), DBU(1,8-Diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh3(triphenylphosphane), SM (starting material), Hex (hexane), NCS(N-chlorosuccinimide), r.t. (room temperature), DCE (dichloroethane), FA(formic acid), CHCl₃ (Chloroform), BnBr (benzyl bromide), HCl (hydrogenchloride), equiv (equivalent), DSC (bis(2,5-dioxopyrrolidin-1-yl)carbonate), RH (relative humidity), QL (quantitation limit), RRT(relative retention time), RS (related substances).

Example 1 Synthesis of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide(i) Synthesis of Intermediate A:

To a solution of tert-butylN-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl] carbamate(16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoylpropanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105° C. for 8 h, cooled to r.t., concentrated under reduced pressure, andpurified by silica gel chromatography (EA/PE, 1/9) to give 17.5 g (97%)of tert-butylN-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamateas a white solid.

(ii) Synthesis of Intermediate B:

To a solution of tert-butylN-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate(17.6 g, 53.4 mmol, 1.0 equiv) in DCM (120 mL) was added TFA (24 mL).The mixture was stirred at room temperature overnight and concentratedunder reduced pressure. The mixture was then poured into ethanol (50 mL)and water (5 mL) and the pH was adjusted to 12 with sodium hydroxidesolution (2 N). The mixture was then extracted with dichloromethane (200mL) three times. The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure to give 11.2 g of(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as abrown oil.

(iii) Synthesis of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide:

To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (6.1 g, 48.4mmol, 1.0 equiv) in DMF (300 mL) were added DIEA (12.6 g, 97.5 mmol, 2.0equiv), HOAt (19.8 g, 145.8 mmol, 3.0 equiv), and EDCI (28 g, 146.1mmol, 3.0 equiv). The mixture was stirred for 15 min, and(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (11.2g, 48.9 mmol, 1.0 equiv) was then added. The mixture was then stirredfor 3 h, diluted with DCM, washed with NH₄Cl solution three times, driedover sodium sulfate, concentrated under reduced pressure, and purifiedby silica gel chromatography (EA/PE, 74/26) to give an intermediateproduct. The intermediate product was triturated with a mixture of EAand PE (1/10) to afford 14.5 g (88%) of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideas a white solid. LRMS (ES) m/z 338 (M+H). ¹H-NMR: (DMSO, 300MHz, ppm):δ 8.41 (1H, d, J=8.4 Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d,J=7.9 Hz), 5.53 (1H, q, J=8.3 Hz), 3.84 (3H, s), 3.13-2.81 (4H, m), 2.44(1H, dd, J=7.9, 4.7 Hz), 1.95 (1H, m), 1.33 (3H, t, J=7.5 Hz).

Example 2 Preparation of an Exemplary Formulation

FIG. 1 presents a flow chart illustrating Unit Operations in thepreparation of a formulation described herein.

(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were delumped with ahand sieve. Magnesium stearate was delumped with a hand sieve.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were mixed in a highshear granulator, and a wet granulation step was performed, followed bywet milling, drying and dry milling. The resulting solid mixture wasblended with microcrystalline cellulose and croscarmellose sodium.Finally, the resulting mixture was blended with magnesium stearate toafford a formulation comprising(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

Example 3 Preparation of Non-Coated Tablet

FIG. 2 presents a flow chart illustrating Unit Operations in thepreparation of a non-coated tablet described herein.

(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were delumped with ahand sieve. Magnesium stearate was delumped with a hand sieve.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were mixed in a highshear granulator, and a wet granulation step was performed, followed bywet milling, drying and dry milling. The resulting solid mixture wasblended with microcrystalline cellulose and croscarmellose sodium. Theresulting mixture is blended with magnesium stearate. This final mixtureis then compressed into tablets to afford non-coated tablets.

Example 4 Preparation of Coated Tablet

FIG. 3 presents a flow chart illustrating Unit Operations in thepreparation of a coated tablet described herein.

(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were delumped with ahand sieve. Magnesium stearate was delumped with a hand sieve.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,microcrystalline cellulose, mannitol, croscarmellose sodium,hydroxypropylcellulose, and sodium lauryl sulfate were mixed in a highshear granulator, and a wet granulation step was performed, followed bywet milling, drying and dry milling. The resulting solid mixture wasblended with microcrystalline cellulose and croscarmellose sodium. Theresulting mixture is blended with magnesium stearate. This final mixtureis then compressed into tablets to afford non-coated tablets. Thesenon-coated tablets are then coated with Opadry White QX to afford coatedtablets.

Example 5 2.5 mg Formulation

Tablets comprising 5 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 1 % 2.5 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 5.0 2.53-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 54.0 27.0 MicrocrystallineCellulose, Filler 20.0 10.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 1.5 (AC-Di-Sol) Hydroxypropyl Cellulose, NF Binder 2.01.0 (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 1.0 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 5.5 NF(Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 1.0(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 0.5 TOTALTablet Core 100.00 50.00 Film Coating Opadry QX White 21A180025 3.0 1.5Total Film Coated Tablet 103.0 51.5

Example 6 5 mg Formulation

Tablets comprising 5 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 2 % 5 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 5.0 5.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 54.0 54.0 MicrocrystallineCellulose, Filler 20.0 20.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 3.0 (AC-Di-Sol) Hydroxypropyl Cellulose, NF Binder 2.02.0 (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 2.0 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 11.0NF (Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 2.0(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 1.0 TOTALTablet Core 100.00 100.00 Film Coating Opadry QX White 21A180025 3.0 3.0Total Film Coated Tablet 103.0 103.0

Example 7 10 mg Formulation

Tablets comprising 10 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 3 % 10 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 5.0 10.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 54.0 108.0 MicrocrystallineCellulose, Filler 20.0 40.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 6.0 (AC-Di-Sol) Hydroxypropyl Cellulose, Binder 2.0 4.0NF (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 4.0 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 22.0NF (Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 4.0(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 2.0 TOTALTablet Core 100.00 200.00 Film Coating Opadry QX White 21A180025 3.0 6.0Total Film Coated Tablet 103.0 206.0

Example 8 20 mg Formulation

Tablets comprising 20 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 4 % 20 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 20.0 20.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 44.0 44.0 MicrocrystallineCellulose, Filler 15.0 15.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 3.0 (AC-Di-Sol) Hydroxypropyl Cellulose, Binder 2.0 2.0NF (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 2.0 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 11.0NF (Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 2.0(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 1.0 TOTALTablet Core 100.00 100.00 Film Coating Opadry QX White 21A180025 3.0 3.0Total Film Coated Tablet 103.0 103.0

Example 9 40 mg Formulation

Tablets comprising 40 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 5 % 40 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 20.0 40.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 44.0 88.0 MicrocrystallineCellulose, Filler 15.0 30.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 6.0 (AC-Di-Sol) Hydroxypropyl Cellulose, Binder 2.0 4.0NF (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 4.0 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 22.0NF (Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 4.0(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 2.0 TOTALTablet Core 100.00 200.00 Film Coating Opadry QX White 21A180025 3.0 6.0Total Film Coated Tablet 103.0 206.0

Example 10 7 mg Formulation

Tablets comprising 7 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process.

TABLE 6 % 7 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 10 7.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 50.0 35.0 MicrocrystallineCellulose, Filler 19.0 13.3 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 2.1 (AC-Di-Sol) Hydroxypropyl Cellulose, Binder 2.0 1.4NF (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 1.4 (Kolliphor)Fine Grade Extra-Granular Microcrystalline Cellulose, Filler 11.0 7.7 NF(Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.0 1.4(AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 0.7 TOTALTablet Core 100.00 70.00 Film Coating Opadry QX White 21A180025 3.0 2.1Total Film Coated Tablet 103.0 72.1

Example 11 40 mg Formulation

Tablets comprising 40 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere prepared according to the process of Example 4, a flowchart ofwhich is shown in FIG. 3. The following ingredients and quantities wereused in this process

TABLE 7 % 40 Item Description Function (w/w) mg/tablet Intra-Granular(R)-N-(5-(5-ethyl-1,2,4-oxadiazol- API 10 40.03-yl)-2,3-dihydro-1H-inden-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide APIMannitol USP (Mannogen EZ SD) Filler 50.0 200.0 MicrocrystallineCellulose, Filler 19.0 76.0 NF (Avicel PH 101) Croscarmellose Sodium NFDisintegrant 3.0 12.0 (AC-Di-Sol) Hydroxypropyl Cellulose, Binder 2.08.0 NF (Klucel EXF) Sodium Lauryl Sulfate NF Surfactant 2.0 8.0(Kolliphor) Fine Grade Extra-Granular Microcrystalline Cellulose, Filler11.0 44.0 NF (Avicel PH 102) Croscarmellose Sodium NF Disintegrant 2.08.0 (AC-Di-Sol) Magnesium Stearate, Non Bov NF Lubricant 1.0 4.0 TOTALTablet Core 100.00 400.00 Film Coating Opadry QX White 21A180025 3.012.0 Total Film Coated Tablet 103.0 412.0

Example 11 Long-term Stability of 5 mg Formulation

Tablets comprising 5 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideas described in Example 6. The tablets were packaged in 30 cc whiteround-wide mouth HDPE bottles with induction seal and 28 mm Securx cap,SG-75M liner. Each bottle contained 40 tables. The tablets were storedfor 12 months at 30° C.+/−2° C. and 65% RH+/−5% RH. After the 12 monthsperiod the tablets were analyzed for appearance, potency, presence ofunknown compounds, ability to release the active ingredient upondissolution, and water content. Results are shown in Table 8.

TABLE 8 Test Acceptance Criteria Results Appearance white to off-white,round, white, round, film-coated tablet film-coated tablet Potency(mean) 90%-110% of label claim 101.7% LC (% LC) based on 5 mg (R)-N-(5-(5-ethyl-1,2,4-oxadiazol- 3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H- pyrazole-4-carboxamide Unspecified UnknownReport Results <QL (RRT 0.89) Compounds % RS Related Substance ReportResults <QL Total % RS Dissolution, 10 min N/A  98% released (mean)Dissolution, 20 min N/A 101% released (mean) Dissolution, 30 min N/A101% released (mean) Dissolution, 45 min N/A 101% released (mean)Dissolution, 60 min N/A 101% released (mean) Dissolution, infinity N/A102% released (mean) Water Content N/A 1.5% RRT: relative retention timeas determined by HPLC % RS: percentage of related substance asdeterminded by HPLC surface area

Example 12 Long-Term Stability of 40 mg Formulation

Tablets comprising 40 mg of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideas described in Example 9. The tablets were packaged in 30 cc whiteround-wide mouth HDPE bottles with induction seal and 28 mm Securx cap,SG-75M liner. Each bottle contained 40 tables. The tablets were storedfor 12 months at 30° C.+/−2° C. and 65% RH+/−5% RH. After the 12 monthsperiod the tablets were analyzed for appearance, potency, presence ofunknown compounds, ability to release the active ingredient upondissolution, and water content. Results are shown in Table 9.

TABLE 9 Test Acceptance Criteria Results Appearance white to off-white,oval, white, oval, film-coated tablet film-coated tablet Potency (mean)90%-110% of label claim 103.6% LC (% LC) based on 40 mg (R)-N-(5-(5-ethyl-1,2,4-oxadiazol- 3-yl)-2,3-dihydro-1H- inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide Unspecified Unknown Report Results <QL (RRT0.89) Compounds % RS Related Substance Report Results <QL Total % RSDissolution, 10 min N/A  90% released (mean) Dissolution, 20 min N/A 97% released (mean) Dissolution, 30 min N/A  99% released (mean)Dissolution, 45 min N/A 100% released (mean) Dissolution, 60 min N/A100% released (mean) Dissolution, infinity N/A 101% released (mean)Water Content N/A 1.2% RRT: relative retention time as determined byHPLC % RS: percentage of related substance as determinded by HPLCsurface area

Biological Example B-1 Myofibril Assays

To evaluate the effect of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideon the ATPase activity of full-length cardiac myosin in the context ofthe native sarcomere, skinned myofibril assays were performed. Bovinecardiac myofibrils were obtained by homogenizing bovine cardiac leftventricular tissue in the presence of a detergent such as triton X-100.Such treatment removes membranes and a majority of the solublecytoplasmic proteins but leaves intact the cardiac sarcomericacto-myosin apparatus. Myofibril preparations retain the ability tohydrolyze ATP in a Ca²⁺ regulated manner. ATPase activities of suchmyofibril preparations in the presence and absence of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewere assayed at Ca²⁺ concentrations activating to a defined fraction ofthe maximal rate (i.e., 25%, 75%).(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewas assessed for their ability to inhibit the steady-state ATPaseactivity of bovine cardiac myofibrils using pyruvate kinase and lactatedehydrogenase (PK/LDH)-coupled enzyme system. This assay regeneratesmyosin-produced ADP into ATP by oxidizing NADH, producing an absorbancechange at 340 nm. Prior to testing(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide,the bovine cardiac myofibrils were assessed for their calciumresponsiveness and the calcium concentration that achieves either a 50%(pCa₅₀) or 75% (pCa₇₅) activation of the myofibril system was chosen asthe final condition for assessing the inhibitory activity of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.All enzymatic activity was measured in a buffered solution containing 12mM PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid), 2 mM magnesiumchloride at pH 6.8 (PM 12 buffer). Final assay conditions were 1 mg/mLof bovine cardiac myofibrils, 4 U/mL pyruvate kinase, 6 U/mL lactatedehydrogenase, 50 μM ATP, 0.1 mg/mL BSA (bovine serum albumin), 10 ppmantifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP, 0.6 mM EGTA, and an amountof CaCl₁₂ sufficient to achieve either 50% or 75% activation of themyofibril ATPase activity. Results for(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideare provided in Table A.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewas prepared in accordance with the synthetic procedures describedherein.

TABLE A CDMF75 IC₁₅ (μM) CDMF75 IC₅₀ (μM) 0.4 1.4

Biological Example B-2 Myocyte Assays (i) Preparation Of Adult CardiacVentricular Rat Myocytes:

Adult male Sprague-Dawley rats were anesthetized and the hearts werequickly excised, rinsed and the ascending aorta was cannulated.Continuous retrograde perfusion was initiated on the hearts at aperfusion pressure of 60 cm H₂O. Hearts were first perfused with anominally Ca²±-free modified Krebs solution of the followingcomposition: 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH₂PO₄, 0.6 mM Na₂HPO₄, 1.2mM MgSO₄, 12 mM NaHCO₃, 10 mM KHCO₃, 30 mM taurine, 5.5 mM glucose and10 mM Hepes (all Sigma). This medium is not recirculated and iscontinually aerated with a 95% O₂/5% CO₂ mixture. After approximately 3minutes the heart was perfused with a modified Krebs buffer supplementedwith collagenase (Worthington) and 12.5 μM final calcium concentration.The heart was removed from the cannulae after the heart appearedblanched and soft in appearance. The atria and vessels were removed andthe ventricles were gently dissected into smaller pieces with forceps.The tissue was homogenized by repeated pipette trituration and thecollagenase reaction was stopped by 10% bovine calf serum (BCS),sedimentation and resuspension in perfusion buffer containing 5% BCS and12.5 uM CaCl₂. Myocytes were made calcium tolerant by stepwise additionof a CaCl₂ solution to a final concentration of 1.2 mM. Cells were thenwashed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5mM MgCl, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl₂, pH 7.4). Cellswere kept for 60 min at 37° C. prior to initiating experiments and usedwithin 5 hrs of isolation. Preparations of cells were used only if cellsfirst passed QC criteria by demonstrating a contractile response tostandard (>150% of basal) and isoproterenol (ISO; >250% of basal)treatment. Additionally, only cells whose basal contractility wasbetween 3 and 8% were used in subsequent experiments with compounds.

(ii) Adult Ventricular Myocyte Contractility Experiments:

Aliquots of myocytes in Tyrode's buffer were placed in perfusionchambers (series 20 RC-27NE; Warner Instruments) complete with heatingplatforms. Myocytes were allowed to attach, the chambers were heated to37° C., and the cells were perfused with 37° C. Tyrode's buffer.Myocytes were field stimulated at 1 Hz in with platinum electrodes (20%above threshold). Only cells that had clear striations and werequiescent prior to pacing were used for contractility experiments. Todetermine basal contractility, myocytes were imaged through a 40×objective. Using a variable frame rate (60-240 Hz) charge-coupled devicecamera, the images were digitized and displayed on a computer screen ata sampling speed of 240 Hz (IonOptix Milton, Mass.). Once cellcontraction was stable over time,(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide(0.01-15 μM) was perfused into the chambers on the myocytes for 5minutes. Contractility of the myocytes and contraction and relaxationvelocities were then recorded using edge detection.

(iii) Contractility Analysis:

Five or more individual myocytes were tested from two or more differentmyocyte preparations. For each cell, twenty or more contractilitytransients at basal (defined as 1 min prior to compound infusion) andafter compound addition (defined as 5 min after starting compoundperfusion), were averaged and compared. These average transients wereanalyzed using the IonWizard software (IonOptix) to determine changes indiastolic length and fractional shortening. Fractional shortening wascalculated as: ((resting length−length at peak contraction) divided bythe resting length). The percent change in fractional shortening frombaseline was calculated as: ((post-dose fractional shortening/basalfractional shortening)*100). The percent reduction in fractionalshortening from baseline was calculated as: (100-percent change infractional shortening from baseline). Maximum contraction and relaxationvelocities (um/sec) was also determined. Results from individual cellsare averaged and the SEM calculated.

The effect of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideon the fractional shortening (FS) of the myocytes is shown in Table B.

TABLE B % FS Concentration (% reduction from # of cells (μM) baseline) ±SEM tested 5 67.4 ± −5.8 5 % FS = Average of each cell's (post baselinepercent peak height/pre-baseline percent peak height) × 100

Biological Example B-3 Echocardiography Assessment of AcutePharmacodynamic Effect in Rat Cardiac Contractility

Assessment of in vivo cardiac function by echocardiography was performedin male Sprague Dawley rats under isoflurane (1-3%) anesthesia. 2-DM-mode images of the left ventricle were acquired in the parasternallong-axis view before, during, and after administration of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideby continuous IV infusion or oral gavage. In vivo fractional shorteningwas determined by M-mode image analysis with the following calculation:((End diastolic diameter−end systolic diameter)/end diastolicdiameter×100). For continuous IV infusion experiments, three pre-dosebaseline M-mode images were taken at 1 minute intervals prior toinfusion of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewas formulated in 50% Propylene Glycol (PG): 16% Captisol: 10%dimethylacetamide (DMA) and delivered via a jugular vein catheter at therate of 1 mL/kg/h. During infusion, M-mode images were taken at 5 minuteintervals. The infusion stopped when fractional shortening reached up toa 60% reduction from baseline. Blood samples were taken to determine theplasma concentration of(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.Data was reported as an estimated IC₅₀ value, which is the concentrationat which fractional shortening is 50% of the pre-dose baselinecontractility. The IC₅₀ results are summarized in Table C.

TABLE C IC₅₀ (Mean ± S.D., μM) 7.2 ± 0.20

For oral dosing studies, three pre-dose baseline M-Mode images weretaken at 1 minute intervals prior to compound administration.(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamidewas formulated in a 0.5% hydroxypropyl methylcellulose 2910 (HPMC 2910):0.1% Tween 80 suspension and delivered as a single dose (5 mL/kg) byoral gavage. Rats were lightly anesthetized for M-Mode echocardiographymeasurements at select time points over a 24 hour period. Different doselevels were evaluated for(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.The compound effect on cardiac fractional shortening at the highest doseevaluated is presented in Table D as a percent reduction of baselinefractional shortening (=100%).

TABLE D FS FS (% reduction from baseline) (% reduction from baseline)Dose at 1-2 h post dose at 4 h post dose (mg/kg) (Mean ± S.D.) (Mean ±S.D.) 2 43 ± 9 31 ± 9

Concurrent with echocardiography measurements, blood samples were takento determine the corresponding(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamideplasma concentration. The data in Table E summarizes the estimated IC₅₀and IC₁₀ values, which is the concentration at which fractionalshortening is 50% and 10% of the pre-dose baseline contractility,respectively.

TABLE E IC₅₀ (μM) IC₁₀ (μM) 7.9 0.8

All documents, including patents, patent application and publicationscited herein, including all documents cited therein, tables, anddrawings, are hereby expressly incorporated by reference in theirentirety for all purposes.

While the foregoing written description of the compounds, uses, andmethods described herein enables one of ordinary skill in the art tomake and use the compounds, uses, and methods described herein, those ofordinary skill in the art will understand and appreciate the existenceof variations, combinations, and equivalents of the specific embodiment,method, and examples herein. The compounds, uses, and methods providedherein should therefore not be limited by the above-describedembodiments, methods, or examples, but rather encompasses allembodiments and methods within the scope and spirit of the compounds,uses, and methods provided herein.

1. A formulation comprising: (i) (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii) a filler; (iii) a binder; (iv) a disintegrant; (v) a surfactant; and (vi) a lubricant.
 2. The formulation of claim 1, wherein the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrines, and mixtures of any of the foregoing.
 3. The formulation of claim 1 or 2, wherein the binder is selected from the group consisting of arabic gum, acacia gum, alginate, alginic acid, corn starch, copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates. potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxy methyl cellulose, starch, and mixtures of any of the foregoing.
 4. The formulation of any one of claims 1-3, wherein the disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrillin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxy methyl cellulose, and mixtures of any of the foregoing.
 5. The formulation of any one of claims 1-4, wherein the surfactant is selected from the group consisting of cetylpyridine chloride, heptadecaethylene oxycetanol, lecithins, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80 Span 85, polysorbates, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salts of fatty alcohol sulfates, sodium lauryl sulfate, sodium salts of sulfosuccinates, sodium dioctylsulfosuccinate, partial esters of fatty acids with alcohols, glycerine monostearate, glyceryl monooleate, ethers of fatty alcohols with polyoxyethylene, esters of fatty acids with polyoxyethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.
 6. The formulation of any one of claims 1-5, wherein the lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate, behertoyl polyoxyl-8 glycerides, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, polaxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.
 7. The formulation of any one of claims 1-6, wherein the formulation comprises: (i) about 1% by weight to about 80% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii) about 15% by weight to about 90% by weight of the filler; (iii) about 0.1% by weight to about 10% by weight of the binder; (iv) about 1% by weight to about 10% by weight of the disintegrant; (v) about 0.1% by weight to about 10% by weight of the surfactant; and (vi) about 0.1% by weight to about 10% by weight of the lubricant.
 8. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 20% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii) about 70% by weight of the filler; (iii) about 2% by weight of the binder; (iv) about 5% by weight of the disintegrant; (v) about 2% by weight of the surfactant; and (vi) about 1% by weight of the lubricant.
 9. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 10% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii) about 80% by weight of the filler; (iii) about 2% by weight of the binder; (iv) about 5% by weight of the disintegrant; (v) about 2% by weight of the surfactant; and (vi) about 1% by weight of the lubricant.
 10. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 5% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii) about 85% by weight of the filler; (iii) about 2% by weight of the binder; (iv) about 5% by weight of the disintegrant; (v) about 2% by weight of the surfactant; and (vi) about 1% by weight of the lubricant.
 11. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 20% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii-1) about 44% by weight of mannitol; (ii-2) about 26% by weight of microcrystalline cellulose; (iii) about 2% by weight of hydroxypropyl cellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight of magnesium stearate.
 12. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 10% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii-1) about 50% by weight of mannitol; (ii-2) about 30% by weight of microcrystalline cellulose; (iii) about 2% by weight of hydroxypropyl cellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight of magnesium stearate.
 13. The formulation of any one of claims 1-7, wherein the formulation comprises: (i) about 5% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (ii-1) about 54% by weight of mannitol; (ii-2) about 31% by weight of microcrystalline cellulose; (iii) about 2% by weight of hydroxypropyl cellulose; (iv) about 5% by weight of croscarmellose sodium; (v) about 2% by weight of sodium lauryl sulfate; and (vi) about 1% by weight of the magnesium stearate.
 14. The formulation of any of the preceding claims, wherein the formulation is for oral administration.
 15. The formulation of any of the preceding claims, wherein the formulation is for administration once daily.
 16. A tablet comprising: (i) a core having a total core weight comprising: (a) an intra-granular component comprising: (a-i) (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii) an intra-granular filler; (a-iii) an intra-granular binder; (a-iv) an intra-granular disintegrant; and (a-v) an intra-granular surfactant; and (b) an extra-granular component comprising: (b-i) an extra-granular filler; (b-ii) an extra-granular disintegrant; and (b-iii) an extra-granular lubricant; and optionally (ii) a coating layer comprising a coating agent.
 17. The tablet of claim 16, wherein the intra-granular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrines, and mixtures of any of the foregoing.
 18. The tablet of claim 16 or 17, wherein the intra-granular binder is selected from the group consisting of arabic gum, acacia gum, alginate, alginic acid, corn starch, copolyvidone, polyvinylpyrrolidone, gelatin, glyceryl behenate, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hypromellose, lactose, polyvinyl alcohol, povidone, polyethylene oxide, polyacrylates, potato starch, pregelatinized starch, sodium alginate, sodium starch, sodium carboxy methyl cellulose, starch, and mixtures of any of the foregoing.
 19. The tablet of any one of claims 16-18, wherein the intra-granular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrillin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxy methyl cellulose, and mixtures of any of the foregoing.
 20. The tablet of any one of claims 16-19, wherein the intra-granular surfactant is selected from the group consisting of cetylpyridine chloride, heptadecaethylene oxycetanol, lecithins, polyoxyethylene stearate, nonoxynol 9, nonoxynol 10, octoxynol 9, sorbitan fatty acid esters, Span 20, Span 40, Span 60, Span 80, Span 85, polysorbates, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, sodium salts of fatty alcohol sulfates, sodium lauryl sulfate, sodium salts of sulfosuccinates, sodium dioctylsulfosuccinate, partial esters of fatty acids with alcohols, glycerine monostearate, glyceryl monooleate, ethers of fatty alcohols with polyoxyethylene, esters of fatty acids with polyoxyethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®), benzalkonium chloride, ethoxylated triglycerides, and mixtures of any of the foregoing.
 21. The tablet of any one of claims 16-20, wherein the extra-granular filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, kaolin, corn starch, maize starch, starch derivatives, pregelatinized starch, calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, compressible sugar, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, lactitol, lactose, dextrose, maltose, sucrose, glucose, fructose, saccharose, raffinose, dextrates, trehalose, maltodextrines, and mixtures of any of the foregoing.
 22. The tablet of any one of claims 16-21, wherein the extra-granular disintegrant is selected from the group consisting of alginic acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium. microcrystalline cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrillin potassium, pregelatinized starch, partially hydrolyzed starch, sodium carboxymethyl starch, starch, sodium alginate, sodium carboxy methyl cellulose, and mixtures of any of the foregoing.
 23. The tablet of any one of claims 16-22, wherein the extra-granular lubricant is selected from the group consisting of hydrogenated castor oil, magnesium stearate, glyceryl monostearate, calcium stearate, glyceryl behenate, glycerol distearate, glyceryl dipalmitostearate, behenoyl polyoxyl-8 glycerides, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mineral oil, polyethylene glycol, polaxamer, sodium lauryl sulfate, and mixtures of any of the foregoing.
 24. The tablet of any one of claims 16-23, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 1% to about 80% of the total core weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii) about 10% to about 80% of the total core weight of the intra-granular filler; (a-iii) about 0.1% to about 10% of the total core weight of the intra-granular binder; (a-iv) about 0.1% to about 5% of the total core weight of the intra-granular disintegrant; and (a-v) about 0.1% to about 5% of the total core weight of the intra-granular surfactant; and (b) an extra-granular component comprising: (b-i) about 5% to about 15% of the total core weight of the extra-granular filler; (b-ii) about 0.1% to about 5% of the total core weight of the extra-granular disintegrant; and (b-iii) about 0.1% to about 5% of the total core weight of the extra-granular lubricant.
 25. The tablet of any one of claims 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 20% of the total core weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 44% of the total core weight of mannitol; (a-ii-2) about 15% of the total core weight of microcrystalline cellulose; (a-iii) about 2% of the total core weight of hydroxypropyl cellulose; (a-iv) about 3% of the total core weight of croscarmellose sodium; and (a-v) about 2% of the total core weight of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 11% of the total core weight of microcrystalline cellulose; (b-ii) about 2% of the total core weight of croscarmellose sodium; and (b-iii) about 1% of the total core weight of magnesium stearate.
 26. The tablet of any one of claims 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 10% of the total core weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 50% of the total core weight of mannitol; (a-ii-2) about 19% of the total core weight of microcrystalline cellulose; (a-iii) about 2% of the total core weight of hydroxypropyl cellulose; (a-iv) about 3% of the total core weight of croscarmellose sodium; and (a-v) about 2% of the total core weight of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 11% of the total core weight of microcrystalline cellulose; (b-ii) about 2% of the total core weight of croscarmellose sodium; and (b-iii) about 1% of the total core weight of magnesium stearate.
 27. The tablet of any one of claims 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 5% by weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 54% by weight of mannitol; (a-ii-2) about 20% by weight of microcrystalline cellulose; (a-iii) about 2% by weight of hydroxypropyl cellulose; (a-iv) about 3% by weight of croscarmellose sodium; and (a-v) about 2% by weight of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 11% by weight of microcrystalline cellulose; (b-ii) about 2% by weight of croscarmellose sodium; and (b-iii) about 1% by weight of magnesium stearate.
 28. The tablet of any one of claims 16-27, comprising a coating layer comprising a coating agent.
 29. The tablet of claim 28, wherein the coating agent is selected from the group consisting of Opadry QX White 21A180025, Opadry I, and Opadry II.
 30. The tablet of claim 28 or 29, wherein the coating agent is Opadry QX White 21A180025.
 31. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 2.5 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 27 mg of mannitol; (a-ii-2) about 10 mg of microcrystalline cellulose; (a-iii) about 1 mg of hydroxypropyl cellulose; (a-iv) about 1.5 mg of croscarmellose sodium; and (a-v) about 1 mg of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 5.5 mg of microcrystalline cellulose; (b-ii) about 1 mg of croscarmellose sodium; and (b-iii) about 0.5 mg of magnesium stearate.
 32. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 20 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 44 mg of the total core weight of mannitol; (a-ii-2) about 15 mg of the total core weight of microcrystalline cellulose; (a-iii) about 2 mg of the total core weight of hydroxypropyl cellulose; (a-iv) about 3 mg of the total core weight of croscarmellose sodium; and (a-v) about 2 mg of the total core weight of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 11 mg of the total core weight of microcrystalline cellulose; (b-ii) about 2 mg of the total core weight of croscarmellose sodium; and (b-iii) about 1 mg of the total core weight of magnesium stearate.
 33. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 5 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 54 mg of mannitol; (a-ii-2) about 20 mg of microcrystalline cellulose; (a-iii) about 2 mg of hydroxypropyl cellulose; (a-iv) about 3 mg of croscarmellose sodium; and (a-v) about 2 mg of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 11 mg of microcrystalline cellulose; (b-ii) about 2 mg of croscarmellose sodium; and (b-iii) about 1 mg of magnesium stearate.
 34. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 40 mg of the total core weight of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 88 mg of the total core weight of mannitol; (a-ii-2) about 30 mg of the total core weight of microcrystalline cellulose; (a-iii) about 4 mg of the total core weight of hydroxypropyl cellulose; (a-iv) about 6 mg of the total core weight of croscarmellose sodium; and (a-v) about 4 mg of the total core weight of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 22 mg of the total core weight of microcrystalline cellulose; (b-ii) about 4 mg of the total core weight of croscarmellose sodium; and (b-iii) about 2 mg of the total core weight of magnesium stearate.
 35. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 10 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 108 mg of mannitol; (a-ii-2) about 40 mg of microcrystalline cellulose; (a-iii) about 4 mg of hydroxypropyl cellulose; (a-iv) about 6 mg of croscarmellose sodium; and (a-v) about 4 mg of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 22 mg of microcrystalline cellulose; (b-ii) about 4 mg of croscarmellose sodium; and (b-iii) about 2 mg of magnesium stearate.
 36. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 7 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 35 mg of mannitol; (a-ii-2) about 13.3 mg of microcrystalline cellulose; (a-iii) about 1.4 mg of hydroxypropyl cellulose; (a-iv) about 2.1 mg of croscarmellose sodium; and (a-v) about 1.4 mg of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 7.7 mg of microcrystalline cellulose; (b-ii) about 1.4 mg of croscarmellose sodium; and (b-iii) about 0.7 mg of magnesium stearate.
 37. The tablet of claim 16-24, wherein the core comprises: (a) an intra-granular component comprising: (a-i) about 40 mg of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (a-ii-1) about 200 mg of mannitol; (a-ii-2) about 76 mg of microcrystalline cellulose; (a-iii) about 8 mg of hydroxypropyl cellulose; (a-iv) about 12 mg of croscarmellose sodium; and (a-v) about 8 mg of sodium lauryl sulfate; and (b) an extra-granular component comprising: (b-i) about 44 mg of microcrystalline cellulose; (b-ii) about 8 mg of croscarmellose sodium; and (b-iii) about 4 mg of magnesium stearate.
 38. A process for making the tablet of any one of claims 16-37, wherein the process comprises: (1) preparing granules comprising (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide the intra-granular filler, the intra-granular binder, the intra-granular disintegrant, and the intra-granular surfactant; (2) milling the granules comprising (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the intra-granular filler, the intra-granular binder, the intra-granular disintegrant, and the intra-granular surfactant to form the intra-granular component; (3) blending the intra-granular component with the extra-granular filler, the extra-granular disintegrant, and the extra-granular lubricant to form a final blend mixture; (4) compressing the final blend mixture to form the core; (5) optionally coating the core with the coating layer.
 39. The process of claim 38, wherein preparing granules comprising (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide the intra-granular filler, the intra-granular binder, the intra-granular disintegrant, and the intra-granular surfactant comprises a wet granulation step.
 40. The process of claim 38 or 39, wherein the wet granulation step further comprises a wet milling step.
 41. The process of any one of claims 38-40, wherein preparing granules comprising (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide the intra-granular filler, the intra-granular binder, the intra-granular disintegrant, and the intra-granular surfactant further comprises drying the granules.
 42. The process of any one of claims 38-41, comprising coating the core with the coating layer.
 43. A method of treating heart disease in a subject in need thereof, comprising administering to the subject the formulation of any one of claim 1-15, or the tablet of any one of claim 16-37.
 44. The method of claim 43, wherein the heart disease is hypertrophic cardiomyopathy (HCM).
 45. The method of claim 44, wherein the HCM is obstructive or nonobstructive or is associated with a sarcomeric and/or non-sarcomeric mutation.
 46. The method of claim 43, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF). 